Comparative reactivity of different types of stable cyclic and acyclic mono- and diamino carbenes with simple organic substrates

Article abstract of DOI:10.1021/ja412981x

A series of stable carbenes, featuring a broad range of electronic properties, were reacted with simple organic substrates. The N,N-dimesityl imidazolylidene (NHC) does not react with isocyanides, whereas anti-Bredt di(amino)carbene (pyr-NHC), cyclic (alkyl)(amino)carbene (CAAC), acyclic di(amino)carbene (ADAC), and acyclic (alkyl)(amino)carbene (AAAC) give rise to the corresponding ketenimines. NHCs are known to promote the benzoin condensation, and we found that the CAAC, pyr-NHC, and ADAC react with benzaldehyde to give the ketone tautomer of the Breslow intermediate, whereas the AAAC first gives the corresponding epoxide and ultimately the Breslow intermediate, which can be isolated. Addition of excess benzaldehyde to the latter does not lead to benzoin but to a stable 1,3-dioxolane. Depending on the electronic properties of carbenes, different products are also obtained with methyl acrylate as a substrate. The critical role of the carbene electrophilicity on the outcome of reactions is discussed.

Full text of DOI:10.1021/ja412981x

Article
pubs.acs.org/JACS
Comparative Reactivity of Different Types of Stable Cyclic and
Acyclic Mono- and Diamino Carbenes with Simple Organic
Substrates
David Martin,† Yves Canac,†,‡ Vincent Lavallo,†,§ and Guy Bertrand*,†
†UCSD-CNRS Joint Research Laboratory (UMI 3555), Department of Chemistry and Biochemistry, University of California, San
Diego, La Jolla, California 92093-0343, United States
‡Laboratoire de Chimie de Coordination, (CNRS, UPR 8241), 31077 Toulouse, France
§Department of Chemistry, University of California at Riverside, Riverside, California 92521, United States
S
* Supporting Information
ABSTRACT: A series of stable carbenes, featuring a broad range of electronic properties, were reacted with simple organic
substrates. The N,N-dimesityl imidazolylidene (NHC) does not react with isocyanides, whereas anti-Bredt di(amino)carbene
(pyr-NHC), cyclic (alkyl)(amino)carbene (CAAC), acyclic di(amino)carbene (ADAC), and acyclic (alkyl)(amino)carbene
(AAAC) give rise to the corresponding ketenimines. NHCs are known to promote the benzoin condensation, and we found that
the CAAC, pyr-NHC, and ADAC react with benzaldehyde to give the ketone tautomer of the Breslow intermediate, whereas the
AAAC first gives the corresponding epoxide and ultimately the Breslow intermediate, which can be isolated. Addition of excess
benzaldehyde to the latter does not lead to benzoin but to a stable 1,3-dioxolane. Depending on the electronic properties of
carbenes, different products are also obtained with methyl acrylate as a substrate. The critical role of the carbene electrophilicity
on the outcome of reactions is discussed.
and non-π-donating alkyl group, results in the more electro-
philic, but also more nucleophilic, cyclic (alkyl)(amino)carbene
(CAAC) c.6 Acyclic carbenes d7 and e8 are more nucleophilic
than their cyclic counterparts a and c since the wider carbene
bond angle decreases the s-character of the lone pair;9
concomitantly, they are more electrophilic due to the free
rotation of the amino group. Several spectroscopic and
electrochemical data confirmed that the electrophilicity10 and
nucleophilicity11,12 of carbenes a−e increase in the order a < b
< c < d < e. The influence of the electronic properties of these
carbenes on their ligand properties and on the catalytic activity
of the corresponding transition metal complexes has been
extensively studied.10−13 In marked contrast, no comparative
studies on the reactivity of different stable amino carbenes with
simple organic substrates have been reported.14 Herein we
discuss the outcome of the reactions of carbenes a−e with alkyl
isocyanides, benzaldehyde, and methyl acrylate.
INTRODUCTION
■
Closed-shell singlet carbenes possess a lone pair of electrons
and an accessible vacant orbital, making them both Lewis acids
and bases, which confer their extreme reactivity.1 Since the
discovery of the first stable singlet carbenes in the late 1980s
and early 1990s,2 it has been well-established that this reactivity
can be tamed by introducing π-donor substituents, which can
make up for the electron deficiency of the carbene center, as
illustrated by carbenes a−e (Figure 1).3 The different
substitution and structural patterns result in carbenes with
different electronic properties. Placing one of the nitrogen
atoms of a classical N-heterocyclic carbene (NHC)4 in the
bridgehead position of a bicyclic scaffold, as shown in the anti-
Bredt NHC b,5 precludes its π-donation thereby enhancing the
π-accepting properties of the carbene center. This structural
modification has no significant effect on the nucleophilicity of
b, compared to classical NHCs, since this property is linked to
the σ-effect of the carbene substituents. In contrast, the
replacement of a σ-electron-withdrawing and π-donating amino
substituent of imidazol-2-ylidene a, by a σ-electron-donating
Received: December 20, 2013
Published: March 17, 2014
© 2014 American Chemical Society
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Figure 1. Carbenes a−e ranked according to their electrophilicity and nucleophilicity.
Figure 2. Adducts of carbenes b−e with isocyanides (no reaction observed with NHC a).
Table 1. Formation and Structure of Model Ketenimines 1a′−e′
a
b
B3LYP/6-31g* level of theory. With isovalue at 0.08 su.
tert-butyl or c-hexyl isocyanide does not react with NHC a, but
cleanly add to carbene b−e, leading to the expected
ketenimines 1b−e (Figure 2). The main spectroscopic features
of 1b−e are the very low-field 13C NMR chemical shift of the
central ketenimine carbon (δ 194−209 ppm) and the intense
infrared absorption at 1980−2000 cm−1 (CN stretching
vibration).
RESULTS AND DISCUSSION
■
Reaction of Carbenes a−e with Isocyanides. It is
already known that carbon monoxide does not react with NHC
a,15 while it reacts with more electrophilic carbenes such as b−
e.16,17 However, with the exception of sterically hindered
CAACs and carbene e, the corresponding ketene was not
observed because it reacts further with a second molecule of
carbene. Isocyanides and CO are isoelectronic but the former
are less π-accepting and more sterically hindered. Conse-
quently, we reasoned that the reaction of isocyanides with
carbenes should lead to stable ketenimines.18 Not surprisingly,
As shown in Table 1, DFT calculations19 are in line with
these experimental results. The reaction of methyl isocyanide
with the model NHC a′ was found to be exothermic by only
−5.1 kcal·mol−1, and due to the entropic cost, the process is
predicted to be endergonic by +5.6 kcal·mol−1 at 298 K. In
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Scheme 1. Mechanism for the Catalytic Benzoin Condensation (Carbene a) and Formation of Compounds 2−5 from Carbenes
b−e
Figure 3. Products from the reaction of carbenes b−e with benzaldehyde; NHC a is known to catalyze the benzoin condensation.
accordance with previous calculations,18a we found that the
hypothetical adduct 1a′ has a pronounced bent geometry (C1−
C2−N1: 134.7°) with a long C1−C2 bond (140 pm). The
HOMO features a C2-centered sp2-hybridized orbital with a
negligible coefficient on C1. As a result, 1a′ is better described
as a zwitterionic compound, in which the π-system connecting
C1 and C2 is highly polarized. In contrast, the additions of the
more electrophilic carbenes b′−e′ are thermodynamically
favored, and the ΔG value decreases as the electrophilicity of
the carbene increases (ΔG from −16 to −30 kcal·mol−1).
Moreover, ketenimines 1b′−e′ have a near-linear geometry
(C1−C2−N1 > 170°), with a typical short C1C2 double
bond (131−133 pm). Their HOMO reflects the destabilizing
effect of the +M amino group(s), as it is an antibonding
combination of the π-system of the C1C2 double bond with
the lone pair orbital of the amino substituent(s). Note that this
destabilizing effect is much less important in the case of the
ketenimine derived from acyclic carbenes (d′, e′) compared to
the cyclic analogues (a′, c′) because 1d′ and e′ can adopt
conformations that minimize the interaction of the amino lone
pair with the π-system of the ketenimine.
latter, known as Breslow intermediates,22 are acyl anion
equivalents and react with a second equivalent of aldehyde to
yield, after a second proton shift, to the benzoin and
regeneration of the carbene. In marked contrast, no evidence
for benzoin condensation occurs with carbenes b−e, even with
an excess of benzaldehyde (Figure 3). Instead, carbenes b−d
cleanly react with benzaldehyde to afford ketones 2b−d, which
are the tautomers of the Breslow intermediates (77−95%
yield). On the other hand, carbene e adds to benzaldehyde to
yield epoxide 3e as a mixture of two diastereomers (8:2 ratio;
81% yield). It is a very rare example of an amino-substituted
epoxide,23 and its stability is in line with the superior π-
accepting properties of e over carbenes a−d. Although storable
as a solid, 3e undergoes a ring opening and a proton shift,
giving rise to enol 4e, within 2 days in solution at room
temperature. Interestingly, when an excess of benzaldehyde was
added to carbene e, dioxolane 5e was isolated in 72% yield and
characterized by NMR and X-ray crystallography. Thus, in
contrast to the benzoin condensation in which a carbon acts as
a nucleophile, the formation of 5e implies the nucleophilic
attack of the oxygen to the second molecule of benzaldehyde.
In the case of imidazolylidenes, such as a, 1,2,4-triazolyl-
idenes, and thiazolinylidenes, which are active catalysts for the
benzoin condensation, the corresponding Breslow intermedi-
ates are highly reactive and usually considered as elusive
species. These compounds, as well as their keto forms and even
Reaction of Carbenes a−e with Benzaldehyde. NHCs
such as a20 are well-established organocatalysts for a variety of
organic reactions,21 such as the benzoin condensation. In such a
reaction, the initial zwitterionic carbene−aldehyde adducts
undergo a proton shift to afford amino enols (Scheme 1). The
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the spirodioxolanes, which are both resting forms of the
Breslow intermediate, have only very recently been charac-
terized.24 The relative robustness of compounds 2b−d and 3e−
5e, especially their reluctance to enter into the catalytic cycle of
the benzoin condensation, is a consequence of the enhanced π-
accepting properties of carbenes b−e compared to those of a.
This statement is supported by simple DFT calculations, as
shown in Table 2. The HOMO of the Breslow intermediate 4a′
is an antibonding combination of the π-system of the enol and
the p orbital of the amino groups. The large and small
coefficients on C2 and C1, respectively, clearly illustrate the
“acyl anion” character of 4a′. There is a good inverse
correlation between the electrophilicity of the carbene and
the nucleophilicity of the corresponding Breslow intermediate.
When the electrophilicity of the carbene increases, the
polarization of the C1C2 double bond and the energy of
the HOMO decrease (4a′ > 4b′ > 4c′ ∼ 4d′ > 4e′).
Reaction of Carbenes a−e with Methyl Acrylate. In
order to complete our study, we investigated the reaction of
carbenes a−e with a Michael acceptor. Keeping in mind that
classical NHCs, such as a, are known to induce the anionic
polymerization of acrylates,20,25 we performed a dropwise
addition of a near-stoichiometric amount of methyl acrylate to a
Table 2. Calculated Structure for Breslow Intermediates
Stemming from the Reaction of Carbenes a′−e′ with H2CO
1
solution of carbene a in THF at −78 °C. 13C, H NMR, and
mass spectrometry indicated the formation of the two isomeric
1:2 carbene−acrylate adducts 6a and 7a (Figure 4). Under the
same experimental conditions, the reaction of carbenes b−e
afforded compounds 8b, 7c, 9d, and 10e, 8e, respectively.
The mechanism of formation of products 6−10 is presented
in Scheme 2. The first step is always a 1,4-addition of
nucleophilic aminocarbenes to methyl acrylate, leading to
zwitterionic intermediates I. Similar to the reaction with
benzaldehyde, the cyclized form 10e of intermediate I was
isolated in the case of the most electrophilic carbene (e) of the
series.8,26 After a week at room temperature, cyclopropane 10e
isomerizes into enamine 8e. With the less electrophilic anti-
Bredt diaminocarbene b, the cyclic form 10 is not observed, the
enamine 8b forms instantaneously. Using the even less
electrophilic imidazolylidene a, the ene-diamine 8a is not
observed either as it readily reacts with a second equivalent of
methyl acrylate to afford 6a, via intermediate III. Note that no
reaction occurs when an excess of methyl acrylate was added to
8e,b. In the case of carbenes a, c, and d, the 1,3-zwitterionic
intermediates I react with a second equivalent of methyl
acrylate to form the 1,5-zwitterions II. With the more
electrophilic carbene d, II undergoes a ring closure, affording
cyclopentane derivative 9d, whereas with carbenes a and c, a
1,4-proton shift leads to 7a,c.
CONCLUSION
■
From this comparative study, it can be concluded that the
reactivity of imidazol-2-ylidenes, which are by far the most
popular carbenes, is not representative for the whole range of
stable carbenes that are available. The reactions observed with
very simple organic substrates illustrate the importance of the
electrophilicity of stable singlet carbenes, a property that is
almost irrelevant in the case of classical NHCs, such imidazol-2-
a
b
c
B3LYP/6-31g* level of theory. Mulliken charges. With isovalue at
0.08 su.
Figure 4. Products from the reaction of carbenes a−e with methyl acrylate.
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Scheme 2. Mechanism for the Formation of Compounds 6−10
Ketenimine 1c. t-Butyl isocyanide (0.08 mL, 0.7 mmol) was added
dropwise to a THF solution (5 mL) of c (0.5 mmol) at −78 °C. The
solution was warmed to room temperature and stirred for 2 h. After
evaporation of the solvent and extraction with hexane (10 mL), 1c was
isolated as a yellow oil (0.16 g, 90%). 1H NMR (300 MHz, C6D6): δ =
7.21−7.27 (m, 3 H), 3.76 (sept, J = 6.8 Hz, 1 H), 3.43 (sept, J = 6.7
Hz, 1 H), 2.03 (d, J = 12.3 Hz, 1 H), 1.89 (d, J = 12.3 Hz, 1 H), 1.60
(d, J = 6.7 Hz, 3 H), 1.57 (s, 3 H), 1.44 (s, 6 H), 1.40 (d, J = 7.1 Hz, 6
H), 1.35 (d, J = 6.5 Hz, 3 H), 1.19 (s, 9 H), 1.16 (s, 3 H) ppm. 13C
NMR (75 MHz, C6D6): δ = 209.2 (C), 151.7 (C), 150.7 (C), 137.2
(C), 128.1 (CH), 125.1 (CH), 124.3 (CH), 112.5 (C), 64.5 (C), 59.1
(C), 56.7 (CH2), 40.0 (C), 34.0 (CH), 30.6 (CH3), 30.4 (CH), 29.3
(CH3), 29.0 (CH3), 28.5 (CH3), 26.8 (CH3), 25.9 (CH3), 25.6 (CH3),
25.2 (CH3) ppm. IR (CH2Cl2): ν(CN) 1982 cm−1. HRMS (ESI-TOF)
[M + H]+ calcd for C25H41N2, 369.2364; found, 369.2373.
ylidenes and imidazolin-2-ylidenes. These results should
encourage the organometallic community not to restrict itself
to NHCs but to broaden the range of carbenes they use as
ligands. The recent isolation of two-coordinate neutral zinc,27
manganese,28 and gold29 complexes, thanks to electrophilic
carbene ligands, is a nice illustration of this statement.
EXPERIMENTAL SECTION
■
General. All manipulations were performed under an inert
atmosphere of argon using standard Schlenk techniques. Dry,
oxygen-free solvents were employed. H and 13C NMR spectra were
1
recorded on Varian Inova 300, 400, and 500 MHz or Bruker Avance
300 MHz spectrometers. Carbenes a−e were synthesized according to
literature procedures.5−8,30 Note that carbene d was synthesized
according to Alder et al. by addition of an excess of TMPLi (1.2 equiv)
to the corresponding conjugate acid salt, and d was used in situ, with
no further purification, because of its rapid dimerization. Commercially
available tert-butyl isocyanide, benzaldehyde, and methylacrylate were
dried over MgSO4 and freshly distilled under inert atmosphere.
Ketenimine 1b. Cyclohexyl isocyanide (52 mg, 0.47 mmol) was
added dropwise to a THF solution (2 mL) of b (0.46 mmol) at −78
°C. After 1 h, the solution was warmed to room temperature. The
volatiles were removed under vacuum, and the product was extracted
with hexane. The solvent was evaporated, and 1b was obtained as a 1:1
Ketenimine 1d. A THF solution (15 mL) of d (7.0 mmol) was
prepared in situ from the corresponding amidinium salt and lithium
2,2,6,6-tetramethylpiperidine. The solution was stirred at −78 °C, and
t-butyl isocyanide (1.19 mL, 10.4 mmol) was added dropwise. The
solution was warmed to room temperature over 2 h. After evaporation
of the solvent and extraction with hexane (15 mL), a yellow oil was
isolated, which essentially consisted of a 1:1 mixture of 1d and
1
tetramethylpiperidine (1.4 g, 65%). H NMR (300 MHz, C6D6): δ =
2.34 (s, 12 H), 1.18 (s, 9 H) ppm. 13C NMR (75 MHz, C6D6): δ =
202.1 (C), 118.8 (C), 58.6 (C), 42.7 (CH3), 30.5 (CH3) ppm. IR
(CH2Cl2): ν(CN) 1981 cm−1.
1
mixture of two diastereomers (135 mg; 75% yield). H NMR (500
Ketenimine 1e. t-Butyl isocyanide (0.50 mL, 4.4 mmol) was added
dropwise at −78 °C to a THF solution (10 mL) of e (0.50 g, 2.9
mmol). Then the solution was warmed to room temperature over 1 h.
After evaporation of the solvent and extraction with hexane (10 mL),
MHz, C6D6): δ = 0.94 (m, 1 H), 1.1 (m, 5 H), 1.3−1.4 (m, 12 H),
1.5−1.6 (m, 6 H), 1.8 (br, 3 H), 2.4 (br, 1 H), 2.8 (m, 1 H), 3.0 (m, 1
H), 3.3 (m, 2 H), 3.4 (m, 1 H), 5.6−5.7 (m, 3 H), 3.9 (br, 1 H), 7.1−
7.3 (br, 3 H). 13C NMR (125 MHz, C6D6): δ = 17.6 (CH2), 19.3
(CH2), 21.2 (CH3), 21.3 (CH3), 21.6 (CH3), 21.7 (CH3), 22.18
(CH2), 22.2 (CH2), 22.24 (CH2), 22.30 (CH3), 22.34 (CH3), 22.60
(CH3), 22.64 (CH3), 23.33 (CH2), 23.35 (CH2), 25.80 (CH), 25.82
(CH), 25.9 (CH), 26.40 (CH), 26.42 (CH), 26.65 (CH), 28.60
(CH2), 29.2 (CH2), 30.8 (CH2), 31.07 (CH2), 31.1 (CH2), 48.1
(CH2), 50.7 (CH2), 51.4 (CH2), 52.4 (CH2), 53.0 (CH2), 56.6 (CH2),
63.3 (CH), 64.2 (CH), 111.4 (NCN), 114.9 (NCN), 120.9 (CHaro),
121.7 (CHaro), 121.8 (CHaro), 122.9 (CHaro), 125.2 (CHaro), 125.6
(CHaro), 138.7 (Caro), 139.0 (Caro), 144.7 (Caro), 145.1 (Caro), 147.4
(Caro), 148.1 (Caro), 208.1 (CN), 216.5 (CN) ppm. IR (benzene):
ν(CN) 2013 cm−1. HRMS (FAB) [M + H]+ calcd for C26H40N3,
394.3217; found, 394.3201.
1
1e was isolated as a yellow oil (0.59 g, 80%). H NMR (300 MHz,
C6D6): δ = 3.16 (sept, J = 6.6 Hz, 2 H), 1.23 (s, 9 H), 1.14 (d, J = 6.6
Hz, 12 H), 1.13 (s, 9 H) ppm. 13C NMR (125 MHz, C6D6): δ = 193.6
(C), 94.6 (C), 58.2 (C), 53.0 (CH), 33.7 (C), 30.6 (CH3), 30.4
(CH3), 24.0−22.0 (br s, CH3) ppm. IR (CH2Cl2): ν(CN) 1981 cm−1.
HRMS (ESI-TOF) [M + H]+ calcd for C16H33N2, 253.2638; found,
253.2644.
Ketone 2b. Benzaldehyde (0.05 mL, 0.47 mmol) was added
dropwise at −78 °C to a THF solution (10 mL) of b (0.5 mmol). The
solution was warmed to room temperature over 1 h. After evaporation
of the solvent and extraction with benzene (2 × 10 mL), 2b was
1
isolated as a red oil (150 mg, 82%). H NMR (300 MHz, C6D6): δ =
8.0 (m, 1 H), 7.25−6.80 (m, 7 H), 6.52 (s, 1 H), 4.64 (m, 1 H), 3.69
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(dd, J = 9 and 4 Hz, 1 H), 3.29 (br d, J = 12 Hz, 1 H), 3.23 (br d, J =
13 Hz, 1 H), 3.04−2.87 (m, 3 H), 2.62 (m, 2 H), 1.81 (d, J = 7 Hz, 3
H), 1.32 (d, J = 7 Hz, 3 H), 1.30−1.15 (m, 4H), 1.15 (d, J = 7 Hz, 3
H), 0.94 (d, J = 7 Hz, 3 H) ppm. 13C NMR (125 MHz, C6D6): δ =
193.3 (C), 151.1 (C), 147.0 (C), 144.2 (C), 136.4 (C), 132.4 (CH),
129.1 (CH), 126.9 (CH), 125.0 (CH), 124.6 (CH), 80.3 (CH), 58.6
(CH2), 55.4 (CH2), 49.2 (CH2), 30.4 (CH), 29.5 (CH), 28.7 (CH),
28.4 (CH2), 25.9 (CH3), 24.1 (CH3), 23.9 (CH3), 23.5 (CH3), 22.3
(CH2) ppm. HRMS (FAB) [M + Na]+ calcd for C26H34N2ONa
413.2569; found, 413.2558.
Ketone 2c. Benzaldehyde (0.1 mL, 1.0 mmol) was added dropwise
at −78 °C to a THF solution (10 mL) of c (0.9 mmol). Then the
solution was warmed to room temperature over 1 h. After evaporation
of the solvent and extraction with hexane (10 mL), 2c was isolated as a
yellow solid (0.33 g, 95%). 1H NMR (300 MHz, C6D6): δ = 7.94−7.98
(m, 2 H), 7.04−7.32 (m, 6 H), 5.48 (s, 1 H), 4.82 (sept, J = 6.7 Hz, 1
H), 3.51 (sept, J = 6.7 Hz, 1 H), 2.13 (d, J = 12.3 Hz, 1 H), 1.91 (d, J =
12.3 Hz, 1 H), 1.77 (s, 3 H), 1.58 (d, J = 6.7 Hz, 3 H), 1.50 (d, J = 6.7
Hz, 3 H), 1.41 (d, J = 6.7 Hz, 3 H), 1.40 (d, J = 6.7 Hz, 3 H), 1.35 (s, 3
H), 1.19 (s, 3 H), 1.14 (s, 3 H) ppm. 13C NMR (75 MHz, C6D6): δ =
201.9 (C), 153.8 (C), 149.7 (C), 140.9 (C), 139.6 (C), 132.8 (CH),
129.0 (CH), 128.8 (CH), 127.6 (CH), 125.6 (CH), 125.0 (CH), 79.0
(CH), 63.8 (C), 59.4 (CH2), 41.8 (C), 32.4 (CH), 32.2 (CH), 29.0
(CH3), 28.7 (CH3), 28.4 (CH3), 28.0 (CH3), 27.0 (CH3), 26.7 (CH3),
26.1 (CH3), 25.0 (CH3) ppm. HRMS (EI) [M − H]+ calcd for
C27H36NO 390.2796; found, 390.2804.
Ketone 2d. Benzaldehyde (0.84 mL, 8.3 mmol) was added
dropwise at −78 °C to a THF solution (20 mL) of d (7.5 mmol).
Then the solution was warmed to room temperature and stirred for 2
h. After evaporation of the solvent, the residue was extracted with
hexane (20 mL). This solution was kept at −20 °C overnight, and 2d
precipitated as a beige solid (1.20 g, 77%). 1H NMR (300 MHz,
C6D6): δ = 8.13 (m, 2 H), 7.05−7.16 (m, 3 H), 3.91 (s, 1 H), 2.25 (s,
12 H) ppm. 13C NMR (75 MHz, C6D6): δ = 196.1 (C), 139.8 (C),
133.0 (CH), 129.4 (CH), 129.0 (CH), 88.7 (CH), 41.5 (CH3) ppm.
HRMS (EI) [M − H]+ calcd for C12H17N2O 205.1341; found,
205.1340.
(s, 1 H), 5.25 (s, 1 H), 3.47 (sept, J = 6.6 Hz, 2 H), 1.14 (d, J = 6.6 Hz,
6 H), 1.12 (d, J = 6.6 Hz, 6 H), 0.85 (s, 9 H) ppm. 13C NMR (125
MHz, C6D6): δ = 139.5 (C), 138.6 (C), 129.2 (CH), 129.0 (CH),
128.6 (CH), 128.4 (CH), 127.0 (CH), 105.2 (C), 101.3 (CH), 92.1
(CH), 47.7 (CH), 43.2 (C), 28.3 (CH3), 26.3 (CH3), 26.0 (CH3)
ppm. HRMS (ESI-TOF) [M + H]+ calcd for C25H36NO2, 382.2741;
found, 382.2746.
Reaction of Methyl Acrylate with Carbene a. Methyl acrylate
(0.29 mL, 3.4 mmol) was added dropwise at −78 °C to a solution of a
(2.3 mmol) in THF (5 mL). The solution was warmed to room
temperature and stirred for 2 h. After evaporation of the solvent and
extraction with hexane (10 mL), a 1:1 mixture of the two isomers 6a
1
and 7a was obtained as a yellow oil (0.79 g, 72%). H NMR (300
MHz, C6D6): δ = 6.81 (s, 1 H), 6.78 (s, 1 H), 6.76 (s, 2 H), 6.75 (s, 1
H), 6.74 (s, 1 H), 6.72 (s, 2 H), 5.65 (d, J = 2.5 Hz, 1 H), 5.59 (d, J =
2.5 Hz, 1 H), 5.55 (d, J = 2.5 Hz, 1 H), 5.53 (d, J = 2.5 Hz, 1 H), 3.28
(m, 1 H), 3.25 (s, 3 H), 3.24 (s, 3 H), 3.23 (s, 3 H), 3.16 (s, 3 H), 2.72
(d, J = 11.0 Hz, 1 H), 2.68 (s, 2 H), 2.56 (m, 1 H), 1.50−2.41 (m, 7
H), 2.39 (s, 3 H), 2.36 (s, 6 H), 2.29 (s, 3 H), 2.28 (s, 6 H), 2.23 (s, 3
H), 2.20 (s, 3 H), 2.11 (s, 3 H), 2.10 (s, 3 H), 2.08 (s, 6 H) ppm. 13C
NMR (125 MHz, C6D6): δ = 176.3 (C), 173.9 (C), 173.9 (C), 173.5
(C), 144.5 (C), 144.0 (C), 138.5 (C), 138.4 (C), 138.2 (C), 138.0
(C), 137.8 (C), 137.7 (C), 137.6 (C), 137.5 (C), 137.4 (C), 137.3
(C), 136.2 (C), 134.7 (C), 130.2 (CH), 130.0 (CH), 129.9 (CH),
129.8 (CH), 129.6 (CH), 116.7 (CH), 116.6 (CH), 114.6 (CH),
114.3 (CH), 68.3 (C), 60.5 (CH), 51.0 (CH3), 50.9 (CH3), 50.7
(CH3), 50.6 (CH3), 41.0 (CH), 35.1 (CH), 34.0 (CH2), 32.6 (CH2),
30.9 (CH2), 27.6 (CH2), 21.2 (CH3), 21.1 (CH3), 18.4 (CH3), 18.3
(CH3), 18.2 (CH3) ppm. HRMS (EI) [M]+ calcd for C29H36N2O4,
476.2675; found, 476.2673.
Reaction of Methyl Acrylate with Carbene b. Methyl acrylate
(40 mg, 0.46 mmol) was added at −78 °C to a solution of carbene b
(0.46 mmol) in THF (7 mL). The mixture was stirred 30 min at −78
°C, and an additional hour at room temperature. The solvent was
removed under vacuum, and the residue was extracted with pentane.
The volatiles were removed under vacuum, affording 8b as a red waxy
oil (110 mg, 65%). 1H NMR (125 MHz, C6D6): δ = 7.34−7.19 (m, 3
H), 3.52 (m, 2 H), 3.40 (s, 3 H), 3.45−3.28 (m, 7 H), 2.86 (dt, J = 13
and 3 Hz, 1 H), 2.75 (d, J = 13 Hz, 1 H), 2.14 (m, 1 H), 1.69 (m, 1
H), 1.58 (m, 1 H), 1.48 (d, J = 7 Hz, 3 H), 1.41 (d, J = 7 Hz, 3 H),
1.40−1.20 (m, 1 H), 1.39 (d, J = 7 Hz, 3 H), 1.33 (d, J = 7 Hz, 3 H),
1.07 (dd, J = 7 and 3 Hz, 1 H) ppm. 13C NMR (125 MHz, C6D6): δ =
173.9 (C), 152.1 (C), 148.9 (C), 147.1 (C), 140.9 (C), 128.1 (CH),
125.2 (CH), 124.8 (CH), 79.0 (CH3), 55.4 (CH2), 54.9 (CH2), 50.5
(CH2), 32.1 (CH2), 31.7 (CH2), 29.0 (CH), 28.4 (CH), 28.3 (CH),
24.7 (CH3), 24.6(CH3), 24.2 (CH3), 21.0 (CH2). IR (THF) ν: 1737
(COester) and 1637 (CCenamine) cm−1. HRMS (FAB) [M + Na]+
calcd for C23H34N2O2Na, 393.2518; found, 393.2520.
Epoxide 3e. Benzaldehyde (0.08 mL, 0.7 mmol) was added
dropwise at −78 °C to a solution of e (0.7 mmol) in THF (5 mL).
Then the solution was warmed to room temperature over 1 h. After
evaporation of the solvent and extraction with hexane (10 mL), 3e was
isolated as a mixture of two diastereomers (80/20) as a yellow oil
1
(0.17 g, 81%). Major diastereomer. H NMR (C6D6, 300 MHz): δ =
7.37−7.40 (m, 2 H), 7.00−7.13 (m, 3 H), 3.88 (m, 1 H), 3.46 (m, 1
H), 2.90 (m, 1 H), 1.09 (s, 9 H), 1.04−1.30 (m, 12 H) ppm. 13C NMR
(75 MHz, C6D6): δ = 137.9 (C), 128.6 (CH), 128.2 (CH), 127.7
(CH), 86.3 (C), 63.0 (CH), 53.2 (CH), 50.4 (CH), 39.7 (C), 28.5
1
(CH3), 24.9 (CH3) ppm. Minor diastereomer. H NMR (C6D6, 300
MHz): δ = 7.37−7.40 (m, 2 H), 7.00−7.13 (m, 3 H), 4.11 (1 H), 3.27
(m, 2 H), 0.92 (s, 9 H), 0.81 (d, J = 6.3 Hz, 12 H) ppm. 13C NMR
(C6D6, 75 MHz): δ = 138.3 (C), 128.6 (CH), 127.7 (CH), 127.4
(CH), 84.3 (C), 65.7 (CH), 55.2 (CH), 49.3 (CH), 39.2 (C), 29.1
(CH3), 26.4 (CH3), 26.0 (CH3) ppm. HRMS (ESI-TOF) [M + H]+
calcd for C18H30NO, 276.2322; found, 276.2323.
Reaction of Methyl Acrylate with Carbene c. Methyl acrylate
(0.08 mL, 0.9 mmol) was added dropwise at −78 °C to a solution of c
(0.6 mmol) in THF (5 mL). The solution was warmed to room
temperature and stirred for 2 h. After evaporation of the solvent,
extraction with hexane (10 mL), and purification on silica gel (1:1
mixture of ethyl acetate and hexane as eluent). 7c was isolated as a
colorless oil (0.18 g, 65%). 1H NMR (300 MHz, C6D6): δ = 7.09−7.21
(m, 3 H), 3.69 (m, 1 H), 3.33 (d, J = 11.9 Hz, 1 H), 3.30 (s, 6 H), 3.15
(sept, J = 6.8 Hz, 2 H), 2.27 (m, 2 H), 2.00 (m, 1 H), 1.85 (m, 1 H),
1.77 (s, 2 H), 1.60 (s, 3 H), 1.45 (s, 3H, CH3), 1.24 (d, J = 6.8 Hz, 3
H), 1.22 (d, J = 6.8 Hz, 3 H), 1.20 (d, J = 6.8 Hz, 3 H), 1.17 (d, J = 6.8
Hz, 3 H), 1.03 (s, 3 H), 1.01 (s, 3 H) ppm. 13C NMR (125 MHz,
C6D6): δ = 175.3 (C), 173.5 (C), 157.9 (C), 150.8 (C), 150.7 (C),
134.4 (C), 128.8 (CH), 125.2 (CH), 125.1 (CH), 88.9 (CH), 62.9
(C), 57.5 (CH2), 51.3 (CH3), 51.2 (CH3), 43.4 (CH), 41.6 (C), 32.2
(CH2), 31.8 (CH3), 30.8 (CH3), 30.3 (CH2), 30.2 (CH3), 29.7 (CH3),
28.9 (CH), 27.2 (CH3), 26.5 (CH3), 24.3 (CH3), 24.2 (CH3) ppm.
HRMS (EI) [M]+ calcd for C28H43NO4, 457.3192; found, 457.3176.
Reaction of Methyl Acrylate with Carbene d. Methyl acrylate
(1.06 mL, 11.8 mmol) was added dropwise at −78 °C to a solution of
d (7.8 mmol) in THF (20 mL). Then the solution was warmed to
room temperature and stirred for 2 h. After evaporation of the solvent
Enol 4e. A C6D6 solution (0.5 mL) of epoxide 3e (100 mg) was
1
kept at room temperature in a NMR tube, and according to H and
13C NMR spectroscopy, the enol derivative 4e was quantitatively
1
formed within 48 h. H NMR (300 MHz, C6D6): δ = 8.07 (s, 1 H),
7.28−7.32 (m, 2 H), 7.00−7.09 (m, 3 H), 3.29 (sept, J = 6.3 Hz, 2 H),
1.04 (d, J = 6.3 Hz, 12 H), 0.95 (s, 9 H) ppm. 13C NMR (75 MHz,
C6D6): δ = 153.8 (C), 139.1 (C), 130.6 (CH), 128.4 (CH), 128.3
(CH), 124.6 (C), 49.6 (CH), 36.7 (C), 33.0 (CH3), 23.2 (CH3), 23.0
(CH3) ppm.
Acetal 5e. Benzaldehyde (0.21 mL, 2.1 mmol) was added dropwise
at −78 °C to a solution of carbene e (0.7 mmol) in THF (10 mL).
The solution was warmed to room temperature over 1 h. After
evaporation of the solvent and extraction with hexane (10 mL), 5e was
isolated as an oily residue (0.19 g, 72%). Colorless crystals were
obtained in a hexane solution at −20 °C. mp: 110−112 °C. 1H NMR
(300 MHz, C6D6): δ = 7.63−7.71 (m, 4 H), 6.94−7.13 (m, 6 H), 6.20
5028
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Journal of the American Chemical Society
Article
and extraction with hexane (20 mL), a mixture containing 9d (2
diastereomers in a 3:2 ratio) and tetramethylpiperidine was obtained
as a yellow oil (1.56 g). Cyclopentanes 9d were spectroscopically
characterized without further purification. Major diastereomer. 1H
NMR (500 MHz, C6D6): δ = 3.38 (s, 6 H), 2.36 (s, 6 H), 2.23 (s, 6
H), 1.92−3.00 (m, 6 H) ppm. 13C NMR (125 MHz, C6D6): δ = 175.1
(C), 173.9 (C), 89.5 (C), 51.5 (CH3), 51.4 (CH3), 47.7 (CH), 41.6
(CH), 41.0 (CH3), 39.5 (CH3), 33.7 (CH2), 32.3 (CH2) ppm. Minor
622. (c) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 113, 361−363.
(3) For reviews, see: (a) Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int.
Ed. 2008, 47, 3122−3172. (b) Vignolle, J.; Cattoen, X.; Bourissou, D.
̈
Chem. Rev. 2009, 109, 3333−3384. (c) Melaimi, M.; Soleilhavoup, M.;
Bertrand, G. Angew. Chem., Int. Ed. 2010, 49, 8810−8849. (d) Martin,
D.; Melaimi, M.; Soleilhavoup, M.; Bertrand, G. Organometallics 2011,
30, 5304−5313. (e) Slaughter, L. M. ACS Catal. 2012, 2, 1802−1816.
(4) For reviews, see: (a) N-Heterocyclic Carbenes in Synthesis; Nolan,
S. P., Ed.; Wiley-VCH: Weinheim, Germany, 2006. (b) N-Heterocyclic
Carbenes in Transition Metal Catalysis, Topics in Organometallic
Chemistry; Glorius, F., Ed.; Springer: Berlin, 2007; Vol. 21.
(c) Kantchev, R. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem.,
Int. Ed. 2007, 46, 2768−2813. (d) Vougioukalakis, G. C.; Grubbs, R.
1
diastereomer. H NMR (300 MHz): δ = 3.44 (s, 6 H), 2.49 (s, 6 H),
2.29 (s, 6 H), 1.92−3.00 (m, 6 H) ppm. 13C NMR (125 MHz, C6D6):
δ = 175.5 (C), 174.8 (C), 88.2 (C), 51.4 (CH3), 51.2 (CH3), 50.3
(CH), 41.8 (CH3), 41.3 (CH), 39.7 (CH3), 35.7 (CH2), 29.8 (CH2)
ppm. HRMS (EI) [M]+ calcd for C13H24N2O4, 272.1736; found,
272.1732.
Reaction of Methyl Acrylate with Carbene e. Methyl acrylate
(0.15 g, 1,74 mmol) was added at −78 °C to a THF solution (5 mL)
of carbene e (0.27 g, 1.58 mmol). The solution was warmed to room
temperature and stirred for 30 min. The solvent was removed under
vacuum, and after extraction with hexane, 10e was isolated as a white
powder (0.345 g, 85%). mp: 75−77 °C. 1H NMR (300 MHz, C6D6): δ
= 0.87 (s, 9H), 1.10 (m, 1H), 1.12 (d, J = 6.5 Hz, 3 H), 1.24 (t, J = 6.0
Hz, 6H), 1.33 (d, J = 7.0 Hz, 3H), 1.69 (dd, J = 7.0 and 8.0 Hz, 1H),
1.88 (dd, J = 5.5 and 7.0 Hz, 1H), 3.13 (sept, J = 7.0 Hz, 1H), 3.2
(sept, J = 6.5 Hz, 1H), 3.47 (s, 3H). 13C NMR (125 MHz, C6D6): δ =
20.7 (CH2), 25.5, 26.6, 26.7, 27.1 (CH3), 27.3 (CH), 29.2 (CH3), 38.6
(C), 51.7 (CH3), 53.8 (CH), 54.2 (CH), 65.5 (C), 172.3 (C) ppm.
HRMS (ESI-TOF) [M + H]+ calcd for C15H30NO2, 256.2271; found,
256.2272.
́
H. Chem. Rev. 2010, 110, 1746−1787. (e) Díez-Gonzalez, S.; Marion,
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Carbenes: From Laboratory Curiosities to Efficient Synthetic Tools; Díez-
Gonzal
2011.
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ez, S., Ed.; Royal Society of Chemistry Publishing: Cambridge,
(5) Martin, D.; Lassauque, N.; Donnadieu, B.; Bertrand, G. Angew.
Chem., Int. Ed. 2012, 51, 6172−6175.
(6) (a) Lavallo, V.; Canac, Y.; Prasang, C.; Donnadieu, B.; Bertrand,
G. Angew. Chem., Int. Ed. 2005, 44, 5705−5709. (b) Jazzar, R.;
Dewhurst, R. D.; Bourg, J.-B.; Donnadieu, B.; Canac, Y.; Bertrand, G.
Angew. Chem., Int. Ed. 2007, 46, 2899−2902. (c) Jazzar, R.; Bourg, J.-
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72, 3492−3499.
(7) (a) Alder, R. W.; Blake, M. E.; Oliva, J. M. J. Phys. Chem. A 1999,
103, 11200−11211. (b) Alder, R. W.; Blake, M. E.; Bortolotti, C.;
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(9) For an illustration of this phenomenom, see the Walsh’s
correlation diagram for CH2: Walsh, A. D. J. Chem. Soc. 1953, 2260−
2266.
(10) The π-accepting properties of a stable carbene (and thus its
electrophilicity) can be directly inferred from the 31P and 77Se NMR
chemical shifts of the corresponding carbene•phenylphosphinidene
and carbene•selenium adducts, respectively. (a) Back, O.; Henry-
Ellinger, M.; Martin, C. D.; Martin, D.; Bertrand, G. Angew. Chem., Int.
Ed. 2013, 52, 2939−2943. (b) Liske, A.; Verlinden, K.; Buhl, H.;
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(11) (a) Tolman, C. A. Chem. Rev. 1977, 77, 313−348. (b) Lever, A.
B. P. Inorg. Chem. 1990, 29, 1271−1285. (c) Lever, A. B. P. Inorg.
Chem. 1991, 30, 1980−1985. (d) Fielder, S. S.; Osborne, M. C.; Lever,
A. B. P.; Pietro, W. J. J. Am. Chem. Soc. 1995, 117, 6990−6993.
(e) Perrin, L.; Clot, E.; Eisenstein, O.; Loch, J.; Crabtree, R. H. Inorg.
Chem. 2001, 40, 5806−5811. (f) Chianese, A. R.; Li, X.; Janzen, M. C.;
Faller, J. W.; Crabtree, R. H. Organometallics 2003, 22, 1663−1667.
(g) Hillier, A. C.; Sommer, W. J.; Yong, B. S.; Petersen, J. L.; Cavallo,
L.; Nolan, S. P. Organometallics 2003, 22, 4322−4326. (h) Huynh, H.
V.; Han, Y.; Jothibasu, R.; Yang, J. A. Organometallics 2009, 28, 5395−
5404. (i) Kelly, R. A., III; Clavier, H.; Giudice, S.; Scott, N. M.;
Stevens, E. D.; Bordner, J.; Samardjiev, I.; Hoff, C. D.; Cavallo, L.;
Rearrangement of cyclopropane 10e was monitored by NMR
spectroscopy at room temperature. The enamine 8e was quantitatively
formed within a week as a mixture of two isomers (85/15). Major
isomer. 1H NMR (300 MHz, C6D6): δ = 5.42 (t, J = 7.5 Hz, 1 H), 3.36
(s, 3 H), 3.17 (d, J = 7.5 Hz, 2 H), 3.08 (sept, J = 6.5 Hz, 2 H), 1.14 (s,
9 H), 1.06 (d, J = 6.5 Hz, 12 H) ppm. 13C NMR (125 MHz, C6D6): δ
= 172.2 (C), 156.5 (C), 118.6 (CH), 51.6 (CH3), 50.7 (CH), 36.8
1
(C), 34.9 (CH2), 31.1 (CH3), 22.5 (CH3) ppm. Minor isomer. H
NMR (300 MHz, C6D6): δ = 5.77 (t, J = 7.5 Hz, 1 H), 3.37 (s, 3 H),
3.22 (sept, J = 6.5 Hz, 2 H), 3.10 (d, J = 7.5 Hz, 2 H), 1.11 (s, 9 H),
1.02 (d, J = 6.5 Hz, 12 H) ppm. 13C NMR (125 MHz, C6D6): δ =
172.5 (C), 157.6 (C), 119.3 (CH), 51.6 (CH3), 50.7 (CH), 38.5 (C),
35.5 (CH2), 32.4 (CH3), 24.0 (CH3) ppm.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra; Cartesian coordinates and absolute
energies for all optimized geometries. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
guybertrand@ucsd.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Nolan, S. P. Organometallics 2008, 27, 202−210. (j) Droege, T.;
̈
■
Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 6940−6952. (k) Liske, A.;
Verlinden, K.; Buhl, H.; Schaper, K.; Ganter, C. Organometallics 2013,
32, 5269−5272. (l) Rodrigues, R. R.; Dorsey, C. L.; Arceneaux, C. A.;
Hudnall, T. W. Chem. Commun. 2013, 50, 162−164.
Thanks are due to the NSF (CHE-1316956) for financial
support. D.M. acknowledges the Extreme Science and
Engineering Discovery Environment (XSEDE), which is
supported by NSF (OCI-1053575).
(12) The Tolman electronic parameter (TEP) of a carbene is a
measure of its overall donor properties, which are a convolution of its
nucleophilicity and electrophilicity. According to the TEP values, 2 is a
superior overall donor than 1. As 2 is also more electrophilic, it is
therefore more nucleophilic than 1. Similarly, we can infer that 4 is
more nucleophilic than 3. As nucleophilicity also increases when
replacing an amino substituent by an alkyl group, the nucleophilicity
follows the order 1 < 2 < 3 < 4 < 5.
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