Intermolecular aminocarbonylation of alkenes using concerted cycloadditions of iminoisocyanates

Article abstract of DOI:10.1021/acs.joc.6b02713

The aminocarbonylation of alkenes is a powerful method for accessing the β-amino carbonyl motif that remains underdeveloped. Herein, the development of intermolecular aminocarbonylation reactivity of iminoisocyanates with alkenes is presented. This includes the discovery of a fluorenone-derived reagent, which was effective for many alkene classes and facilitated derivatization. Electron-rich substrates were most reactive, and this indicated that the LUMO of the iminoisocyanate is reacting with the HOMO of the alkene. Computational and experimental results support a concerted asynchronous [3 + 2] cycloaddition involving an iminoisocyanate, which was observed for the first time by FTIR under the reaction conditions. The products of this reaction are complex azomethine imines, which are precursors to valuable β-amino carbonyl compounds such as β-amino amides and esters, pyrazolones, and bicyclic pyrazolidinones. A kinetic resolution of the azomethine imines by enantioselective reduction (s = 13.43) allows access to enantioenriched products. Overall, this work provides a new tool to convert alkenes into β-amino carbonyl compounds.

Full text of DOI:10.1021/acs.joc.6b02713

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Article
Intermolecular Aminocarbonylation of Alkenes using
Concerted Cycloadditions of Imino-Isocyanates
Amanda Bongers, Christian Clavette, Wei Gan, Serge I. Gorelsky, Lyanne Betit, Kaitlyn Lavergne, Thomas
Markiewicz, Patrick J. Moon, Nicolas Das Neves, Nimrat K. Obhi, Amy B. Toderian, and Andre M. Beauchemin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02713 • Publication Date (Web): 21 Dec 2016
Downloaded from http://pubs.acs.org on December 23, 2016
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Intermolecular Aminocarbonylation of Alkenes using Concerted
Cycloadditions of IminoꢀIsocyanates
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Amanda Bongers, Christian Clavette, Wei Gan, Serge I. Gorelsky, Lyanne Betit, Kaitlyn
Lavergne, Thomas Markiewicz, Patrick J. Moon, Nicolas Das Neves, Nimrat K. Obhi, Amy B.
Toderian, André M. Beauchemin*
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Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular
Sciences, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
ABSTRACT: The aminocarbonylation of alkenes is a powerful method for accessing the βꢀ
amino carbonyl motif that remains underdeveloped. Herein, the development of intermolecular
aminocarbonylation reactivity of iminoꢀisocyanates with alkenes is presented. This includes the
discovery of a fluorenoneꢀderived reagent, which was effective for many alkene classes and
facilitated derivatization. Electronꢀrich substrates were most reactive, and this indicated that the
LUMO of the iminoꢀisocyanate is reacting with the HOMO of the alkene. Computational and
experimental results support a concerted asynchronous [3+2] cycloaddition involving an iminoꢀ
isocyanate, which was observed for the first time by FTIR under the reaction conditions. The
products of this reaction are complex azomethine imines, which are precursors to valuable βꢀ
amino carbonyl compounds such as βꢀamino amides and esters, pyrazolones, and bicyclic
pyrazolidinones. A kinetic resolution of the azomethine imines by enantioselective reduction
(s=13−43) allows access to enantioenriched products. Overall, this work provides a new tool to
convert alkenes into βꢀamino carbonyl compounds.
INTRODUCTION
The βꢀamino carbonyl is a key structural motif in many biologically active acyclic and
(hetero)cyclic compounds, most notably βꢀamino acid derivatives and βꢀpeptides. An additional
methylene unit provides proteolytic stability to βꢀamino carbonyl compounds compared to their
natural αꢀamino carbonyl analogs. This has made the βꢀamino carbonyl motif abundant in
therapeutics, agrochemicals, peptidomimetics, and natural products.1 Drugs such as metamizole,
ondansetron, and βꢀlactam antibiotics are representative examples (Figure 1). βꢀPeptides have
also become essential peptidomimetics, and the design of unique foldamer structures has made
them exciting targets in drug discovery and proteomics.2 The prevalence and importance of βꢀ
amino carbonyl compounds has resulted in intense research towards their synthesis.
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HO2C
Ph
O
O
O
O
N
n
Ph
H2N
N
CO2H
N
N
N
S
H
H
H
H
OH
Bestatin
protease inhibitor
-Peptides
peptidomimetics
Penicillin G
-lactam antimicrobial
building blocks:
O
O
Me
O
N
N
N
OMe
H
H2N
OH
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(R)- 3-Homoalanine
Ondansetron
Methylphenidate
N
antiemetic
psychostimulant
NH
Me
O
O
Me
H2N
H2N
OMe
Ph
N
N
N
Me
O
Ph
O
OH
O
OH
N
2,3-Cyclic, trans
SO3H
Me
Me
Metamizole
acute pain treatment
O
Cocaine
alkaloid
Figure 1. Examples of important βꢀamino carbonyl compounds.
The synthesis of βꢀamino carbonyl compounds from readily available starting materials has
attracted considerable attention.3,4 Many successful approaches use naturally abundant αꢀamino
acids as substrates,5 and many synthetic methodologies involve forming either the CꢀN bond, or
CαꢀCβ bond.6 The preparation of enantiopure βꢀamino carbonyl compounds has also stimulated
intense research over the last three decades.7,8 Many of these methods are useful if the products
are simple and substrates are readily available. However, some strategic disconnections remain
underdeveloped for the synthesis of βꢀamino carbonyl compounds, such as reactions involving
CꢀH activation and the aminocarbonylation of alkenes. Alkenes are the substrates of choice in
many amination reactions because they are abundant and generally inexpensive, but they are
rarely used to form βꢀamino carbonyl compounds. This approach is simple yet potentially
powerful in βꢀamino carbonyl synthesis, with the potential to generate complexity rapidly.
There are few methods available for the aminocarbonylation of alkenes, and intermolecular
reactivity is quite rare. An early adopted and useful approach is the formal [2+2] cycloaddition of
olefins with isocyanates to yield βꢀlactams (Scheme 1). Electronꢀrich alkenes react with many
isocyanates, but unactivated alkenes require the use of the highly electrophilic chlorosulfonyl
isocyanate (CSI).9 Notably, this process is used in industry to synthesize diverse βꢀlactams that
can be precursors to βꢀamino acids, agrochemicals, and drugs.10 However, this approach has
limitations, including the high reactivity of the cycloadducts and the toxicity and promiscuous
reactivity of CSI.9eꢀf
Scheme 1. Intermolecular [2+2] aminocarbonylation reactions of alkenes with chlorosulfonyl
isocyanate
A more direct approach to alkene aminocarbonylation has been developed in intramolecular
systems using palladium (II) catalysis.11 Racemic reactions affording 5ꢀ and 6ꢀmembered
azacycles are well developed, and have been used in the synthesis of several natural products,12
and a highly enantioselective variant has been developed by Sasai and coworkers.13 An
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alternative was reported by Livinghouse et al.,14 using an intramolecular aminoꢀmetallation
approach followed by a subsequent acylation of the alkylzinc intermediate. However, there are
few reports of intermolecular variants (Scheme 2), and no reports of enantioselective
intermolecular alkene aminocarbonylation reactions. The palladiumꢀassisted aminocarbonylation
of alkenes was pioneered in the 1980s by Hegedus and coworkers.15a They found that
stoichiometric Pd(II) enabled intramolecular aminopalladation, and that under appropriate
conditions CO insertion was favored over side reactions. The intermediate reacted with methanol
to form βꢀamino methyl esters. Shortly after these studies, Hegedus reported the intermolecular
aminocarbonylation of ethylene with the lithium salts of indole and skatole in the presence of CO
and methanol (Scheme 2a).15bꢀc The yields of βꢀNꢀindolyl methyl esters were modest, and
intermolecular reactivity with other olefins was not reported. In 2015, Liu communicated
catalytic conditions for the intermolecular aminocarbonylation of unactivated alkenes and
styrenes (Scheme 2b).16 Stoichiometric hypervalent iodine is essential to the activation and
turnover of the palladium catalyst, and this method gives a wide scope of racemic Nꢀprotected βꢀ
amino methyl esters. However, currently only terminal alkenes are reactive (providing β3ꢀ
substituted amino esters), and the reaction is limited to acidic nitrogen nucleophiles.
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Scheme 2. Pd Assisted/catalyzed intermolecular aminocarbonylation of alkenes
Our efforts toward alkene aminocarbonylation arose from our early interest in concerted, metalꢀ
free amination reactions with hydrazine derivatives.17 While attempting an alkene
hydroamination reaction with a Bocꢀprotected hydrazide, an unexpected intramolecular
aminocarbonylation reaction was observed (Equation 1).17b,f Thermolysis of the hydrazide
provided the aminoꢀisocyanate reactive intermediate,18 which underwent a concerted [3+2]
cycloaddition to give the βꢀamino carbonyl product. This highlighted the potential of this
reactivity for the aminocarbonylation of alkenes, using an amphoteric aminoꢀisocyanate reagent
that contains both the nitrogen and carbonyl functionalities.
In contrast to common isocyanates, which are bulk industrial chemicals, Nꢀisocyanates are quite
rare in the literature (Figure 2).19ꢀ21 Containing a nucleophilic amine and an electrophilic
isocyanate carbon, Nꢀisocyanates are amphoteric reactive intermediates that typically cannot be
isolated.22 In fact, aminoꢀisocyanates are known to dimerize at temperatures as low as −40 °C.19a
We set out to develop Nꢀisocyanates as bifunctional reagents for alkene aminocarbonylation.
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Figure 2. Amphoteric reactive intermediates.
9
This preliminary work with aminoꢀisocyanates gave promising results for intramolecular
reactions.17b,f However, intermolecular reactivity was very limited (e.g. norbornene as the
substrate) and the high temperatures required (>150 °C) led mostly to isocyanate dimers and
degradation of the reagent.20b In exploring other types of Nꢀisocyanates, we became interested in
intermolecular reactions of iminoꢀisocyanates (containing a sp2 nitrogen, Figure 2).21 In contrast
to aminoꢀisocyanates, iminoꢀisocyanates should show less propensity to dimerize because of the
reduced nucleophilicity of the nitrogen atom. A single report from Jones describing the
unexpected formation and reactivity of an iminoꢀisocyanate with alkenes warranted further study
(Scheme 3). Jones observed the intermolecular cycloaddition of one in situ generated, hindered
iminoꢀisocyanate with four alkenes and an alkyne, but no yields were provided.21b Arguably, the
potential of this reactivity as an alkene aminocarbonylation strategy was not demonstrated, nor
recognized until recently.
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Scheme 3. Intermolecular aminocarbonylation with iminoꢀisocyanates
Herein, an inꢀdepth study on the use of iminoꢀisocyanates for metalꢀfree, intermolecular alkene
aminocarbonylation is presented. In contrast to Jones, our approach uses hydrazones as blocked
(masked) Nꢀisocyanate precursors,22 and allows for controlled formation of the reactive iminoꢀ
isocyanate intermediate in situ. The scope of this cycloaddition has been thoroughly explored:
many alkene classes react with a variety of hydrazones to provide complex azomethine imines.
Both experimental results and DFT calculations are consistent with a concerted [3+2]
cycloaddition. Importantly, these aminocarbonylation products are useful precursors to a variety
of valuable compounds possessing the βꢀamino carbonyl motif including complex hydrazines,
pyrazolidinones, pyrazolones, and βꢀamino acid derivatives. The kinetic resolution of these
racemic azomethine imines was also developed, allowing the conversion of alkenes into
enantioenriched βꢀamino carbonyl compounds.
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RESULTS AND DISCUSSION
Reaction Development and Optimization of NꢀIsocyanate Precursor.23 In the development of
a useful alkene aminocarbonylation reaction, our approach was to use hydrazones as stable and
easily synthesized iminoꢀisocyanate precursors.21dꢀg However, there are only few accounts that
describe the formation and reactivity of iminoꢀisocyanates, and there were no reports using
hydrazone precursors for Nꢀisocyanate cycloaddition reactions. Thus, the basic structure of the
hydrazone, such as the blocking group or the aldehyde or ketone precursor, were studied for their
effect on overall aminocarbonylation reactivity. Early in this research, optimization of the
hydrazone was focused on preventing 1,3ꢀdipolar cycloaddition of the product azomethine imine
with excess alkene (Scheme 4). Initial studies showed that aldhydrazones were prone to such
crissꢀcross cycloaddition processes,24 forming diastereomeric mixtures and isocyanate
degradation products.
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Scheme 4. Alkene aminocarbonylation reactions with iminoꢀisocyanates: process and possible
side reactions
For simplicity and to prevent these side reactions, symmetrical ketones with increasing bulk were
first studied. The reactivity of several NꢀBoc hydrazones (1aꢀf) was evaluated using norbornene
as substrate (Table 1). Hydrazones with small R groups (1a, Me; 1b, Et) provided the
azomethine imine products in 67ꢀ70% isolated yield, but complete consumption of hydrazone
was observed owing to competing sideꢀreactions. Bulkier hydrazones derived from
adamantanone (1e) and diisopropyl ketone (1f) gave excellent yields of the aminocarbonylation
products. The bulky groups assist in shielding the dipole from a second cycloaddition, and also
help prevent selfꢀreactions of the iminoꢀisocyanate.
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Table 1. Screening of hydrazones (1aꢀf) with increasing bulk for the aminocarbonylation of
norbornene.a
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Entry
R
Hydrazone
Product, Yield (%)b
1
2
3
4
Me
Et
−(CH2)4−
Ph
2a, 70
2b, 67c
2c, 70
2d, 70
1a
1b
1c
1d
5
2e, 95
2f, 95
1e
1f
6
iꢀPr
a
Conditions: hydrazone ([1aꢀf], 1 equiv.), norbornene (10 equiv.) in PhCF3 (0.05 M) heated in a sealed
vial (microwave reactor, 150 °C, 3 h). b Isolated yield. c 15 equiv. norbornene.
The study of iminoꢀisocyanate precursors continued with investigation of the blocking group
(BG). There are two steps in the overall aminocarbonylation reaction: 1) generation of the
reactive iminoꢀisocyanate by expulsion of the blocking group, 2) cycloaddition of the iminoꢀ
isocyanate with the alkene. The nature of the blocking group will affect the concentration of
iminoꢀisocyanate formed in situ at a given temperature, and which step will be rate determining.
Seven blocking groups were tested at a range of temperatures in the reaction of
diisopropylketoneꢀderived hydrazones with excess norbornene (Table 2). In this experiment, all
hydrazones are precursors to the same iminoꢀisocyanate and product. At 150°C, all blocking
groups performed comparably. As the reaction temperature was lowered, the different blocking
groups had a large effect on the product yield. For example, hydrazone 1i (BG=OPh) gave 84%
yield of 2f at 100 °C, whereas 1g (BG=OEt) only provided an 8% yield. At 80 °C, low yields of
2f were obtained with all hydrazones. This is attributed to the difficulty of forming the iminoꢀ
isocyanate at low temperatures, and to the intermolecular aminocarbonylation reaction also
requiring higher temperatures. The blocking groups OPh (entry 4) and OtꢀBu (entry 1) were
chosen for further investigations of hydrazone structure.
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Table 2. Survey of blocking groups for a first generation aminocarbonylation reagent.a
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Yields (%)b
120°C
69
Entry
BG
150°C
99
99
82
92
98
90
90
100°C
23
0
30
84
46
60
46
80°C
7
0
1
2
3
4
5
6
7
1f: OtꢀBu
1g: OEt
1h: OCH2CF3
1i: OPh
1j: SEt
1k: SPh
8
55
85
64
69
69
9
38
11
31
13
1l: N(iꢀPr)2
a Conditions: hydrazone (1fꢀl, 1 equiv.), norbornene (10 equiv.) in PhCF3 (0.05 M) heated in a sealed vial
(microwave reactor, 80ꢀ150 °C, 3 h). b NMR yields using 1,3,5ꢀtrimethoxybenzene as internal standard.
The results with the first generation of hydrazones provided insight on blocking group trends,
possible side reactions, and optimal solvent (see Supporting Information: Table S1). However,
reactions with reagent 1f did not provide high yields of cycloadduct with unactivated alkenes
(e.g. 1ꢀhexene, cycloalkenes, see Table 4). In addition, azomethine imines (2) from these
hydrazones were unsuitable as precursors to the desired βꢀamino acid derivatives. Unfortunately,
we found that 2f was resistant to a broad range of derivatization reactions, likely due to the high
steric shielding that was installed to prevent unwanted dipolar cycloaddition (Equation 2).
Furthermore, the deprotection of the βꢀnitrogen atom was expected to be an additional challenge
due to the need for reducing conditions for NꢀN bond cleavage. A more versatile reagent was
needed in order to access a variety of βꢀamino carbonyl compounds, ideally having a functional
group on the nitrogen that could be easily removed or reduced to form a protecting group.
Second Generation Reagent Discovery and Advantages. With a growing understanding of the
alkene aminocarbonylation reaction and iminoꢀisocyanate intermediate (including DFT results
presented below), studies to develop an improved reagent were initiated. Informative Xꢀray
crystal structures of diispropyl (2f) and diphenyl (3f) azomethine imines showed a staggered
(twisted) geometry of their respective groups,23 which creates a highly shielded environment
around the C=N bond, making these compounds resistant to NꢀN bond cleavage (Figure 3).
Figure 3. XꢀRay crystal structures of azomethine imines
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In designing a new reagent, planar systems were anticipated to provide an azomethine imine
shielded from 1,3ꢀdipolar cycloaddition but not from an approaching nucleophile. One of the
first ketones explored with these criteria was fluorenone. Fluorenoneꢀderived hydrazones are
simple to prepare, and fluorenone is commercially available and inexpensive. Gratifyingly
hydrazone 4 (BG=OPh) showed excellent reactivity under standard conditions with norbornene
at 100 °C, giving 5a in 99% yield (Figure 4). The analysis of an Xꢀray structure of 5a shows near
coꢀplanarity of the fluorenylidene with the dipolar pyrazolone core (torsion angle = −3.15°).23
This allows delocalization of the dipole charge into the fluorenyl group, an effect that should
stabilize the azomethine imine and prevent unwanted dipolar cycloaddition, and also lower the
cycloaddition transition state. The coꢀplanarity also shields the dipole from a second
cycloaddition, and a close CH⋅⋅⋅N proximity is observed in the crystal structure (Figure 4). This
proton is observed by 1H NMR to be shifted by +1 ppm (at ca. 9.0 ppm) from the other aromatic
signals, an effect of the dipole charge delocalization.
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Figure 4. Reactivity of 4 with norbornene and single crystal Xꢀray structure of cycloadduct 5a.
When the initial reactivity of 4 was explored, it was found to outꢀperform all previously tested
iminoꢀisocyanate precursors. Reactivity was observed even with terminal aliphatic alkenes
(Table 3, entries 1ꢀ7). The best yield and regioselectivity for the Markovnikov product 5b was
obtained at a hydrazone concentration of 0.05 M. The resonance stabilized azomethine imine is
effectively blocked from unwanted 1,3ꢀdipolar cycloaddition, and this byꢀproduct was never
observed. Thus, an excess of less reactive alkenes can be used without loss of azomethine imine
yield. Optimization revealed reactivity at 100 °C, which allowed longer reaction times (up to 6
hours) without iminoꢀisocyanate side reactions or degradation (entry 9), and thus maximization
of the yield. In all cases, excellent selectivity for the formation of the Markovnikov product was
obtained. Overall, this selected optimization data shows that hydrazone 4 proved more robust
under the reaction conditions, and could be recovered after the reaction with minimal loss of
mass. This reagent was chosen to further evaluate the limits and scope of this alkene
aminocarbonylation reactivity.
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Table 3. Optimization of reactivity with unactivated alkenes.a
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Ratio
(5:6)
25:1
25:1
25:1
25:1
50:1
>100:1
>100:1
>100:1
>100:1
Entry
R
[ 4] (M)
t (h)
T (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
nꢀC4H9
nꢀC4H9
nꢀC4H9
nꢀC4H9
nꢀC4H9
CH2Si(Me)3
CH2Si(Me)3
C6H5
0.50
0.25
0.10
0.05
0.05
0.05
0.05
0.05
0.05
3
3
3
3
3
3
3
3
6
150
150
150
150
100
150
100
100
100
67 (5b)
67
67
73
57
72 (5c)
81
40 (5d)
64
C6H5
a Conditions: Hydrazone (4, 1.0 equiv.), alkene (10 equiv.) in PhCF3 (0.05 ꢀ 0.50 M) heated at 100ꢀ150 °C for
3ꢀ6 h. b 1H NMR yield of desired regioisomer using 1,3,5ꢀtrimethoxybenzene internal standard.
Aminocarbonylation of Alkenes: Scope and Trends. With the fluorenoneꢀderived iminoꢀ
isocyanate precursor 4 in hand, a large variety of alkene substrates were screened. A selected
scope of the reaction is shown in Table 4, and for additional data and Xꢀray structures see the
Supporting Information. Initial optimized conditions for screening were: 10 equivalents of
alkene, PhCF3 (0.05 M), 100 °C, 3 hours. Different classes of alkenes required further
optimization of reaction conditions, to balance formation of the isocyanate with reactivity of the
substrate. The substrates can be divided into “activated” alkenes, which are either electron rich or
strained (e.g. enol ethers, norbornene), and other alkenes, which are monoꢀsubstituted or
unstrained aliphatic alkenes and styrenes. Cyclic internal alkenes show generally good reactivity,
while linear internal alkenes are less reactive. Surprisingly, a strained cyclopropane yielded no
product, and no reactivity was observed with various alkynes, which may be attributed to steric
hindrance caused by the planar fluorenone group. Overall, Table 4 shows a large scope of
products (5) with unprecedented complexity from the intermolecular aminocarbonylation of
alkenes with the optimized reagent 4. Synthetically useful yields were obtained for a variety of
alkene classes, typically providing crystalline products, with high selectivity for the formation of
the Markovnikovꢀtype products (typically >20:1). Results with the first generation reagent 1f are
provided for comparison purposes.
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Table 4. Selected scope of alkene aminocarbonylation.a
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
t
(h)
3
3
2
Entry
Alkene (# equiv)
Yieldb (%)
84c
2f
T (°C)
1
2
3
(10)
(10)
(2)
100
100
100
1f
4
99
93
5a
4
5
6
7
(10)
(10)
(10)
(10)
80
120
80
3
1
3
3
78
1f
4
2g
5e
2h
5f
86
60d
52d
1f
4
120
8
9
X= 4ꢀOMe
4ꢀOMe
3ꢀOMe
2ꢀOMe
H
(10)
(10)
(5)
(5)
(5)
(10)
(10)
(5)
120
100
100
100
100
120
100
120
120
100
150
150
120
150
100
100
3
3
6
6
6
3
3
3
3
6
3
3
3
3
3
6
43
75
29
72
64
54
48
48
43
23g
73
45
50
38
81
52e
1f
4
2i
5g
5h
5i
5d
5j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4ꢀF
Me
2ꢀBr
3ꢀBr
5k
5l
(5)
5m
5n
5b
5o
5p
5q
5c
5r
4ꢀCF3
R1= nꢀBu
iꢀBu
(10)
(10)
(5)
4
4
Cy
tꢀBu
CH2TMS
(CH2)2OBn
(5)
(10)
(10)
(10)
24
(5)
120
3
66
5s
25
(5)
120
3
56
4
4
5t
26
27
(1)
80
3
93
39
5u
5v
(20)
150
0.3
4
4
28
29
30
31
n=1
n=2
n=3
n=4
(10)
(>50f)
(10)
100
150
100
100
6
3
6
6
76
54
40
54
5w
5x
5y
5z
(10)
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32
33
(5)
100
120
3
2
0
4
4
5aa
5ab
(10)
51d,e
8
9
34
(10)
120
3
31d
10
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4
5ac
a
Conditions: hydrazone (1f or 4, 1.0 equiv.), alkene (typically 5ꢀ10 equiv.), PhCF3 (entry 27: 1.0 M, entry 13:
0.5 M, entry 26: 0.2 M, entries 19, 21, 24: 0.1 M) or neat (entries 4, 6, 8, 29), heated at 80ꢀ150 °C for 1ꢀ6 h.
Reactions above 100 °C are heated in a sealed vial in a microwave reactor. b Isolated yields provided. c NMR yield. d
Mixture of regioisomers (Z:E, 2h=7:1, 5f=14:1, 5ab=6:1, 5ac=1.5:1), major regioisomer (Z) is shown. The
e
f
minimum regioselectivity for other regioisomers is 20:1.
Xꢀray crystal structure obtained for 5r and 5ab.
Cyclohexane used as solvent. g Regioisomer 6n was also isolated in 5% yield.
Derivatization of the Cycloadducts. The azomethine imines synthesized from the second
generation reagent 4 could be converted into βꢀamino amides by reductive NꢀN cleavage (Table
5). This transformation was achieved with Raney nickel and required a borohydride reagent; no
reaction was observed with Raney nickel and hydrogen gas. These βꢀamino amides can be
transformed into βꢀamino esters (Table 5).25a While this derivatization procedure proved efficient
with adducts derived from both cyclic and acyclic alkenes, it should be noted that epimerization
was observed for one of the three bicyclic substrates.
Table 5. Access to βꢀamino amides (7)a and esters (8)b
O
Ra-Ni
NaBH4
(or KBH4)
H2N
O
MeO
O
N
N
SOCl2
MeOH
R2
H
H
N
N
R2
Flu
R2
R1
MeOH
60 °C
60 °C
12 h
R1
R1
Flu
5
7
8
X
O
H
X
O
H
X
O
H
H
N
H
H
N
N
Flu
Flu
Flu
H
H
H
X=NH2: 7a, 85%
X=OMe: 8a, 49%
7c, 59%
7b, 62%
8b, 50%
X
O
X
O
X
O
X
O
H
H
H
N
H
N
N
N
Flu
Flu
Flu
Flu
C6H4(4-OMe)
7f, 75%
8f, 60%
SiMe3
7e, 70%
8e, 64%
Fe
7d, 91%
8d, 89%
7g, 72%
a Conditions: azomethine imine (1 equiv), Raney nickel (slurry in
water), methanol (0.1 M) and either NaBH4 or KBH4 (10.0 equiv)
b
heated at 60 °C in a sealed screwꢀtop flask. Amide 7 added to a
solution of SOCl2 in MeOH at 0 °C, then heated at 60 °C for 12 h.
The Nꢀfluorenyl group (Flu) is a known nitrogen protecting group, and could be removed by
oxidation with DDQ to access the free βꢀamino amide (Equation 3).25b
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Following this work, simpler and milder derivatization protocols were developed. First, an
alternative to the fluorenyl deprotection was pursued. Various nitrogenꢀbased nucleophiles were
screened for their ability to add to the dipole C=N bond and undergo transimination.26 The
desired transimination was achieved with aqueous hydroxylamine, and the resulting free
pyrazolidinone is soluble in water and could be easily separated from the insoluble fluorenone
oxime by filtration (Scheme 5a). The pyrazolidinone then undergoes reductive ring opening with
Raney nickel and H2, and Boc protection allows for easy isolation of the protected βꢀamino
amide (Scheme 5b). The crude pyrazolidinone can also be used directly to synthesize
unsymmetrical azomethine imines, by condensation onto aldehydes following the traditional
approach for their synthesis (Scheme 5c). The latter derivatization to form azomethine imines
allows a comparison with other common approaches for the formation of such 1,3ꢀdipoles.27
Besides similar condensations, azomethine imines have also been formed by the deprotonation of
hydrazonium salts,28 by oxidation of hydrazine derivatives,29 Nꢀalkylation of hydrazone
precursors,30 Cope–type hydroamination of alkynes,17d or generated in situ by a 1,2ꢀproton shift
from a suitable hydrazone.31 The cycloaddition reaction of alkenes and iminoꢀisocyanates
presented herein thus constitutes a complementary route to synthesize these useful 1,3ꢀdipoles.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Derivatization by transimination with NH2OH
a. Nucleophilic deprotection (transimination) with NH2OH
O
aq. NH2OH
O
N
N
N
H
MeOH,
reflux 3-6 h
OH
HN
HN
H
+
then H2O,
filtration
H
H
5a
b. Reductive N-N cleavage & protection:
10a, 99%
(precipitate)
O
Ra-Ni, H2
MeOH
H2N
HN
H
aq. NH2OH;
10a
5a
H2O, filtration
then Boc2O
Boc
H
11a, 66%
(3 steps from 5a)
O
O
O
O
H2N
HN
H2N
H2N
HN
H2N
H
HN
Boc
HN
H
Boc
PMP Boc
Ph
Boc
11b, 86%
(from 5b)
11c, 63%
(from 5g)
11d, 74%
(from 5d)
11e, 52%
(from 5w)
O
c. Condensation onto benzaldehyde:
N
N
H
aq. NH2OH;
PhCHO
10a
5a
Ph
Ph
H2O, filtration
MeOH, rt
H
H
12a, 60%
O
O
N
N
PhCHO
aq. NH2OH;
HN
HN
5p
MeOH, rt
H2O, filtration
Cy
H
12b, 79%
10b
Cy
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Overall, we have demonstrated the value of alkene aminocarbonylation reactions with iminoꢀ
isocyanates for the synthesis of azomethine imines, βꢀamino amides, and other compounds
possessing the βꢀamino carbonyl motif. This was accomplished by the development of efficient
derivatization protocols. The methods are simple and use inexpensive reagents, but can only
provide racemic products. In order to access enantioenriched βꢀamino carbonyl compounds from
alkenes, we investigated the kinetic resolution of azomethine imines by enantioselective
reduction.32
10
11
12
13
14
15
16
17
18
19
20
21
22
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Kinetic Resolution of Azomethine Imines by Enantioselective Reduction. Alkene
aminocarbonylation with iminoꢀisocyanates provides complex azomethine imines, which are
valuable precursors to βꢀamino amides through reduction. However, the intermolecular
aminocarbonylation step is not enantioselective and thus the products are racemic. This is not a
new problem: there are no reports of enantioselective intermolecular alkene aminocarbonylation
reactions in the literature. Thus, the synthesis of enantioenriched βꢀamino carbonyls from the
alkene aminocarbonylation reaction discussed above required the development of new chemistry.
We envisioned a kinetic resolution of azomethine imines by enantioselective reduction,32 using a
chiral Brønsted acid to allow controlled 1,2ꢀreduction of the C=N bond. A similar concept was
demonstrated by Maruoka for nucleophilic additions to acyclic azomethine imines,33 but there
were no reports for the activation of N,N’ꢀcyclic azomethine imines by Brønsted acids, or reports
on their enantioselective reduction. Consequently, this reactivity was explored by screening
chiral phosphoric acid organocatalysts with the Hantzsch ester as a reductant. From the initial
screening, we found that only (R)ꢀTRIP provided sufficient yields of reduced product and high
enantioselectivity. This kinetic resolution by reduction showed high selectivity (s=13ꢀ43) for 15
examples (Figure 5 & Figure 6), typically providing the enantioenriched azomethine imine in
>90% ee.
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58
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60
Figure 5. Kinetic resolution of azomethine imines derived from fluorenone by enantioselective
reduction with (R)ꢀTRIP.
The reduced product (pyrazolidinone) was often isolated at lower enantiomeric purity, and
recrystallized to high ee. This method was applicable for fluorenoneꢀderived azomethine imines
(obtained by alkene aminocarbonylation, Figure 5), and for a variety of ketone and aldehydeꢀ
derived substrates (Figure 6), including those synthesized by the transimination protocol
described above.
O
O
O
2-5 mol% (R)-TRIP
1.4 equiv Hantzsch Ester
N
N
N
N
HN
N
R1
R1
R1
H
R3
R3
R3
PhMe or PhCl
40-80 °C
6 examples
+
R2
R2
R2
R4
R4
R4
13
syn ( )-12
12
85 - >99% ee
66-86% ee
32-45% yield
41-54% yield
O
O
O
O
H
N
H
N
N
N
N
N
N
N
Ar
Ph
Ph
Fur
H
H
H
Ph
Cy
H
H
Me
s = 22-23
s = 13
s = 25
s = 13
2.5 mol% (R)-TRIP, 5 mol% (R)-TRIP,
PhCH3, 40-60 °C PhCl, 60 °C
2.5 mol% (R)-TRIP,
2.5 mol% (R)-TRIP,
PhCl, 80 °C (dr=2:1)
PhCl, 60 °C
Figure 6. Kinetic resolution of unsymmetrical azomethine imines derived from aldehydes and
ketones.
A model of the preꢀtransition state complex accurately predicts enantioselectivity (Scheme 6),
which arises from the sterically favourable approach, featuring dual activation of the rigid
azomethine imine (by the Brønsted acid) and the Hantzsch ester (by the Brønsted base, P=O).34
This method provides unreacted azomethine imine in high ee (e.g. 12b), and an enantioenriched
pyrazolidinone (e.g. 13b) which can be recrystallized to high ee. Further reduction offers
opposite enantiomers of the same βꢀamino amide with no loss in enantiopurity (Scheme 6).
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Scheme 6. From a racemic azomethine imine to enantioenriched βꢀamino amides
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
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31
32
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Recrystallization provided the reduced compound 13b in 98% ee and 58% yield (overall 29% yield from (±)ꢀ
12b).
When combined, the intermolecular alkene aminocarbonylation reaction and derivatization
methodologies are a versatile approach towards enantioenriched azomethine imines,
pyrazolidinones, βꢀamino amides, and other compounds containing the βꢀaminocarbonyl motif.
Aminocarbonylation of Enol Ethers: Scope and Catalysis.35 Enol ethers have electron rich
C=C bonds, and were quickly discovered to undergo facile intermolecular aminocarbonylation
with iminoꢀisocyanates. With reagent 4, reactivity with a variety of enol ethers was observed at
100 °C (Table 6, conditions B). The high reactivity of enol ethers was used to develop conditions
for catalysis of the reaction. It is possible to catalyze the formation of the iminoꢀisocyanate using
a base,36 and catalysis of the overall reaction at 70 °C was successful in cases where Nꢀ
isocyanate formation is the rateꢀ determining step (Table 6, conditions A). In contrast, there was
little effect of adding base when the reaction temperature was 100 °C. Base catalysis enabled the
use of new iminoꢀisocyanate precursors, including aldehydeꢀderived hydrazones, without
unwanted dipolar cycloadditions. In turn, this strategy allowed the synthesis of enol ether
adducts which are inaccessible under normal thermal conditions, since enol ethers are often
sensitive and can degrade under mildly acidic conditions. These results are shown in Table 6.
Table 6. Selected scope of enol ethers with various iminoꢀisocyanate precursors.a
t
(h)
3
2
3
Product,
Yield (%)b
3a, 81
Entry
Equiv
Enol Ether
R5, R6
Cata
T (°C)
1
2
3
10
2
0.67
ꢀ
ꢀ
80
100
70
1f
4
4
3b, 75
Et3N
68
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10
2
10
10
2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
80
100
80
100
130
130
100
70
3
2
3
3
1
1.5
2
2.5
3
2
3
3c, 87
3d, 68
3e, 99
3f, 75
3g, 82
3h, 90
3i, 57
95
1f
4
1f
1d
1m
1n
4
2
2
10
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0.67
10
2
0.67
0.67
Et3N
ꢀ
ꢀ
Et3N
Et3N
80
3j, 70
3k, 77
81
1f
4
100
100
70
2.5
38
16
0.68
Et3N
70
3
3l, 69
4
17
18
19
20
21
22
2
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
100
100
100
100
100
100
2
3
3
3
1
3
3m, 70c
3n, 63
3o, 25
3p, 57
3q, 98d
3r, 86d
4
4
4
4
4
4
0.67
0.67
0.5
2
n=1
n=2
n=3
n=1
n=2
2.5
23
0.67
Et3N
100
3
3s, 76e
4
a Conditions A: hydrazone, enol ether (0.67ꢀ2.0 equiv), Et3N (3 mol %) in PhCF3 (0.1 M) heated at 70ꢀ100 °C for
1ꢀ3 h. B: hydrazone, alkene (2ꢀ10 equiv), in PhCF3 (0.1 M) heated at 80ꢀ130 °C for 1ꢀ3 h. b Isolated yields provided
c
d
are calculated based on the limiting reagent. Enol ether is a mixture of cis/trans, final product is 16:1 anti/syn.
Ring junction hydrogens are anti to the bridge. e Ring junction hydrogens are syn to the CH2OBn.
Synthetic Applications: Pyrazolones. The azomethine imines provided by aminocarbonylation
reactions of enol ethers (3) are closely related to pyrazolones (15): aromatic heterocycles with
applications in medicinal chemistry and agrochemistry.37 Pyrazolones are typically synthesized
from hydrazines and unsaturated carbonyl compounds, or through variations relying on the same
retrosynthetic disconnection.38 In contrast, we envisioned access to pyrazolones from our
azomethine imines by a oneꢀpot reduction/aromatization sequence, to provide a new approach
starting from simple alkenes. The reduction of azomethine imines derived from enol ethers was
first explored using sodium borohydride. Typically, the pyrazolidinone could not be isolated, and
a aqueous NH4Cl workꢀup allowed aromatization by expelling the intrinsic alcohol R1OH
(Figure 7). For hindered substrates, brief heating in the presence of an acid catalyst was required
to obtain the fluorenylꢀprotected pyrazolone.
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Figure 7. Synthesis of pyrazolones (15) from azomethine imines (3).
The fluorenyl protecting group was readily removed from 15a by reduction with Pd/C and H2
(Equation 4). In addition, the hydroxylamine transimination protocol (described above) could be
applied to provide the free pyrazolone 16b in one step directly from the azomethine imine
(Equation 5).
In summary, we developed a twoꢀstep reaction sequence to convert enol ethers into pyrazolones.
The first step is the aminocarbonylation of enol ethers with iminoꢀisocyanates, which occurs
under relatively mild conditions and could be catalyzed by base. To our knowledge, this is the
first report on the use of base catalysis to accelerate the release of an Nꢀisocyanate from a
blocked precursor.21eꢀg This method enabled the synthesis of complex azomethine imines from
enol ethers, which are then readily converted to pyrazolones by reduction or nucleophilic
addition followed by in situ aromatization.
Alkene aminocarbonylation with unsymmetrical iminoꢀisocyanate precursors.39 In order to
access a wider scope of complex azomethine imines, and overcome steric limitations of the
fluorenone reagent, the reactivity of unsymmetrical hydrazones was studied (Table 7). Aldehydeꢀ
derived hydrazones were a particular challenge, because they give more reactive azomethine
imines that can undergo unwanted 1,3ꢀdipolar cycloaddition with excess alkene.
With careful optimization of reaction conditions,39 modest to good yields of aromatic aldehydeꢀ
derived azomethine imines were obtained (12bꢀg). A variety of unsymmetrical ketoneꢀderived
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hydrazones were also explored as iminoꢀisocyanate precursors. These provided good to high
yields of complex ketoneꢀderived azomethine imines (12hꢀv) which are shielded from unwanted
dipolar cycloaddition. While only one stereoisomer was obtained with aldehydeꢀderived
reagents, most reactions with ketoneꢀderived reagents provided stereoisomeric mixtures of
azomethine imines (Z:E = 2:1 to 6:1), with the exception of tꢀbutyl methylketone and 2ꢀ
thiophenyl ketone derived hydrazones providing (Z:E=>20:1, 12k,p,q,s). The latter observation
may be due to a unique chalcogen bonding effect between sulfur and nitrogen,40 favoring this
stereoisomeric product.40d
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Table 7. Aminocarbonylation of unsymmetrical iminoꢀisocyanate precursors.a
a
b
Major isomer (Z) is shown, isolated yields are provided. Hydrazone (BG=OPh, 1.0 equiv), alkene (1.5ꢀ5.0
c
d
e
equiv) or (10 equiv) in PhCF3 (0.05 M) at 130 °C for 1ꢀ3 h (microwave). 5.0 equiv vinyl ferrocene. 1ꢀHexene
used as solvent. f Hydrazone (BG=OtꢀBu) was used, T=150 °C.
A mixture of stereoisomers is obtained with most unsymmetrical ketone derivatives, which is
expected since two iminoꢀisocyanate stereoisomers can be formed under the reaction conditions.
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As illustrated below, the reaction is also influenced by the blocking group released during Nꢀ
isocyanate formation (Equation 6). Improved selectivity is obtained for the Z isomer of 12j in the
presence of PhSH rather than PhOH as a blocking group. Control experiments performed with
pure E and Z isomers show that isomerization occurs under the reaction conditions even in the
absence of PhXH.39 These results show that this reaction is influenced by the presence of
additives, and suggests the reaction could be improved.
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The ability of unsymmetrical iminoꢀisocyanate precursors to react efficiently also provided the
opportunity to explore intramolecular alkene aminocarbonylation. To our knowledge, examples
of intramolecular aminocarbonylation reactions involving sp2 nitrogen atoms have not been
reported. Intramolecular reactivity was first tested with a readily available NꢀBoc hydrazone 17a.
The reaction gave none of the desired azomethine imine product, and byꢀproducts were observed
that result from side reactions of the azomethine imine with the reactive iminoꢀisocyanate.
Norbornene was added to the reaction in an attempt to trap the azomethine imine in situ by 1,3ꢀ
dipolar cycloaddition (Scheme 7). This strategy also served as a competition experiment to
evaluate intermolecular versus intramolecular aminocarbonylation reactivity. Intramolecular
aminocarbonylation followed by intermolecular cycloaddition with the dipolarophile,
norbornene, was expected. Surprisingly, the major product was from an initial intermolecular
reaction with norbornene, followed by an intramolecular dipolar cycloaddition. The structure of
18 was confirmed by Xꢀray crystallography.39
Scheme 7. Intermolecular vs. intramolecular aminocarbonylation competition experiment
Conversely, intramolecular aminocarbonylation was observed with related ketone derived
hydrazones (Equation 7). The products of these reactions are bicyclic azomethine imines, which
proved difficult to isolate due to their instability on silica gel.
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G
iven the complexity of the azomethine imines formed with this method and our interest in
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reaction cascades, this provided the opportunity to explore their cycloaddition reactivity further.
Azomethine imines are wellꢀknown for reactivity in 1,3ꢀdipolar cycloadditions, typically
proceeding faster with electronꢀpoor dipolarophiles.41 Since intermolecular alkene
aminocarbonylation reactions are more favorable with electronꢀrich alkenes, this allowed for
alkene aminocarbonylation / 1,3ꢀdipolar cycloaddition cascades in which both partners can be
added at the beginning of the reaction (Table 8). This approach proved efficient when
electronically differentiated reagents were used, to give products 20aꢀf in 24−81% yields. The
structure of 20a was confirmed by Xꢀray crystallography.23
Table 8. Cascade alkene aminocarbonylation / 1,3ꢀdipolar cycloaddition.a
a Hydrazone (1.0 equiv), electron rich alkene (10 equiv norbornene
or b1 equiv vinyl ferrocene) and dipolarophile (Nꢀphenyl maleimide or
dimethyl acetylenedicarboxylate, 10 equiv) in PhCF3 (0.05 M) at
120°C for 6ꢀ12 h (microwave). Isolated yields and anti:syn
stereochemistry are provided.
Various nucleophilic additions to the C=N bond of the azomethine imine were also studied.
Vinyl magnesium bromide added to 12p with high diastereoselectivity, with the formation of a
fully substituted carbon center alpha to the pyrazolidinone ring system, to give 62% yield of 13c
(Equation 8). Grignard addition to the aldehydeꢀderived substrate 12f also proceeded with good
diastereoselectivity and yield (Equation 9). In addition, KꢀSelectride was found to be effective
for a highly diastereoselective reduction (>25:1) to give 13e in 72% yield.
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Finally, treatment of azomethine imines with a Brønsted base (secondary or primary amine) and
heat provides pyrazolones (Equation 10). This likely occurs through isomerization of the
azomethine imine followed by favorable aromatization, and has been reported with other N,N’ꢀ
cyclic azomethine imines when using tꢀBuOK.42
Visualization of the Iminoꢀisocyanate by IR spectroscopy. In order to visualize the iminoꢀ
isocyanate and obtain direct support of its involvement in the proposed cycloaddition, we
became interested in reaction monitoring with IR spectroscopy. Isocyanates have signature peaks
in the infrared sp region, typically from 2200ꢀ2300 cmꢀ1, and IR spectroscopy is a valuable tool
to study the reactivity of carbonꢀsubstituted isocyanates, such as the kinetics of deblocking
(isocyanate release) or polymerization (isocyanate consumption).18c,43 However, this has not
been applied to iminoꢀisocyanates due to several challenges: detection of the iminoꢀisocyanate at
the low concentration during the reaction, and sideꢀreactions such as dimerization that occur at
higher concentrations. In fact, only few Nꢀisocyanates have been observed experimentally, in
matrices at low temperatures,19b,44 but some hindered Nꢀisothiocyanates show moderate stability
at room temperature and have thus been characterized by IR and NMR spectroscopy.45
To perform the analysis, a flowꢀIR instrument equipped with an injector was used, which is
designed for analysis of liquid solutions and reaction mixtures. The entire analysis was
performed in a glove box for control of moisture and oxygen. The study began with the first
generation reagent 1f under conditions of base catalysis. The spectra of 1f at room temperature
with or without Et3N showed no significant differences. The reagent was then heated to 90 °C in
the presence of Et3N, and samples of the mixture were injected into the IR detector. Upon
heating, the colourless mixture became dark orange, which suggests formation of a conjugated π
system. The first sample after 17 min at 90 °C showed a new peak corresponding to the NCO
asymmetric stretch at 2201 cm–1 (Figure 8). This peak is in good agreement with the reported
values of 2220 cm–1 for Me2NꢀNCO and 2221 cm–1 for N3ꢀNCO in Argon matrices,19b,44c and
does not correspond to CO2 (2337 cm–1) or CO (2138 cm–1 ), both being possible products of
iminoꢀisocyanate degradation.
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Figure 8. IR visualization of iminoꢀisocyanate formation from 1f.
The fluorenoneꢀderived reagent 4 was then studied (Scheme 8). The hydrazone solubilized to a
yellow solution upon heating at 90 °C, and then became dark ruby red. Analysis of the sample
after 10 min showed a new peak at 2191 cm–1, corresponding to the asymmetric NCO stretch of
the conjugated iminoꢀisocyanate (see Supporting Information). This peak does not match the
expected frequency of the fluorenone azine (1600ꢀ1650 cm–1), a red byꢀproduct that is observed
in reactions at higher temperatures.46 Norbornene was added to the reaction mixture after 20
minutes, and the mixture immediately returned to a pale yellow solution. Prompt analysis of the
reaction mixture revealed no peak at 2191 cm–1.
Scheme 8. IR visualization of iminoꢀisocyanate from reagent 4
This study provided the first direct evidence for the intermediacy of the iminoꢀisocyanate in
alkene aminocarbonylation reactions, and the first characterization of such species by IR
spectroscopy. More broadly, this method has the potential to be a valuable technique for studying
the formation of Nꢀisocyanates in other cycloadditions or cascades reactions.21fꢀg
Mechanistic Studies and DFT Calculations. In this research on alkene aminocarbonylation, it
became clear that cycloaddition reactions of iminoꢀisocyanates are unique in their reactivity
preferences and in the products formed. In comparison to chlorosulfonyl isocyanate, which is
purely electrophilic, iminoꢀisocyanates are amphoteric and exhibit moderate electrophilicity and
nucleophilicity. In addition, the literature shows that other isoelectronic reactants (e.g. azides,
nitrones) undergo different cycloaddition reactivity compared to iminoꢀisocyanates.47 For
example, nitrones preferably undergo 1,3ꢀdipolar cycloadditions with electron deficient
dipolarophiles employing the HOMO of the nitrone and LUMO of the alkene. The transition
state for alkene aminocarbonylation is similar to the 1,3ꢀdipolar cycloaddition: the iminoꢀ
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isocyanate cycloaddition is concerted and asynchronous (see below for computational and
experimental evidence), and partial charges exist on the amphoteric reactant. However, the
iminoꢀisocyanate cycloaddition occurs preferentially with electronꢀrich alkenes, signifying that
the LUMO of the iminoꢀisocyanate is important.
9
Given the novelty of the cycloaddition, the reaction was studied both computationally and
experimentally. Computational results were obtained early in the reaction development process
to provide further information about the geometry of the aminocarbonylation transition state, and
help guide the survey of the reaction scope. The lowest energy transition state structures for the
reactions of both ethylene and norbornene with the simple iminoꢀisocyanate derived from
acetone are shown below (Figure 9).
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Figure 9. Calculated transition states (B3LYP/TZVP) for the intermolecular aminocarbonylation
of dimethyl iminoꢀisocyanate with A) ethylene and B) norbornene. Bond distances (Å) are
shown.
A concerted asynchronous transition state is observed in both models, with the C−C bond more
formed than the N−C bond. This result is in agreement with the preference for the formation of
Markovnikov products observed experimentally. Insight into the potential energy surface of the
reaction was also acutely needed, since this cycloaddition has the peculiarity of forming a dipole
from a neutral isocyanate reactive intermediate. These types of cycloadditions should be less
thermodynamically favorable when compared to dipolar cycloadditions, and could
consequentially be more limited from a synthetic perspective. The calculated potential energy
surface for the reaction of dimethyl iminoꢀisocyanate with norbornene is shown in Figure 10.
Gibbs free energies of activation were calculated to be 35.5 kcal/mol in vacuum and 36.3
kcal/mol in MeOH solvent. These values are relative to the reactants, and the calculations
suggest that formation of the iminoꢀisocyanate is endergonic. From this intermediate, activation
energies for the cycloaddition were calculated to be 28.9 kcal/mol in the gas phase, and 25.8
kcal/mol in MeOH. These values are consistent with reactions requiring heating to proceed. The
results also show the iminoꢀisocyanate is destabilized in MeOH compared to vacuum, whereas
the dipole product is stabilized. Qualitatively, this result is significant because one equivalent of
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a blocking group is released under the reaction conditions and able engage in hydrogen bonding.
This result is also consistent with the changes in azomethine imine ratios observed in the
presence of PhSH or PhOH additive (Equation 6). Given this, the driving force for the reaction
calculated in MeOH (ꢀGr = –6.7 kcal/mol) is likely more appropriate than the value determined
in the gas phase (ꢀGr = 5.6 kcal/mol). Since these values were determined for the reaction of
norbornene, which benefits from some strain release, this suggests that the reaction is close to
thermoneutrality, an observation that could be important if more stable alkenes are used as
reagents. In agreement with this, some crossover was observed in a cycloreversion /
aminocarbonylation experiment (Equation 11).
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Figure 10. Gibbs free energies (kcal/mol, 298K) for the reaction of norbornene (C7H10) and
dimethyl iminoꢀisocyanate in vacuum (red line) and in methanol (black line). TS = transition
state.
In addition to the computational studies,23 stereospecific reactions of cisꢀ and transꢀβꢀ
methylstyrene provided experimental support for a concerted cycloaddition reaction (Scheme 9).
The aminocarbonylation of cisꢀβꢀmethylstyrene provided the syn product (5v) in 24% yield,
while transꢀβꢀmethylstyrene gave a 1:1 mixture of anti adducts 5v and 6v in 52% combined
yield.
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Scheme 9. Reactions with cisꢀ and transꢀβꢀmethylstrene provide experimental support for a
concerted cycloaddition
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Beyond providing strong support for a concerted cycloaddition, these results highlight that more
stable alkenes can react with reagent 4. In fact, many of the alkenes surveyed in the context of
exploratory studies provided the alkene aminocarbonylation products, which testifies of the
reliability of this approach. Extensions of this reactivity, including the cycloaddition reactions of
iminoꢀisocyanates with imines, and of iminoꢀisothiocyanates with alkenes and imines were not
included in this article due to space considerations.40d Overall, these results indicate a strong
propensity of amphoteric isocyanates to engage in concerted cycloaddition reactions.
CONCLUSION
The aminocarbonylation reaction of iminoꢀisocyanates with alkenes is a powerful strategy for
accessing many complex azomethine imines and βꢀamino carbonyl compounds from simple
starting materials. An advantage to this approach is that it yields stable, isolable and typically
crystalline azomethine imines. Systematic variations on the hydrazone reagent allowed the
identification of aminocarbonylation reagent 4, possessing OPh as an optimal blocking group to
form the iminoꢀisocyanate in situ, and a planar fluorenylidene group that provides sufficient
steric shielding to prevent [3+2] reactions of the desired azomethine imine product with excess
alkene. Gratifyingly, this reactivity proceeds with a wide range of alkenes and hydrazones, and
for reactive alkenes tertiary amine bases were found to accelerate the formation of the
Nꢀisocyanate and the overall process. Perhaps more importantly, the fluorenoneꢀderived reagent
allows for a variety of derivatization reactions, including reductive protocols for NꢀN bond
cleavage and transformation of the cycloadducts into βꢀamino carbonyl compounds. There are
several ways to remove the fluorenyl auxiliary, including by oxidation with DDQ or via a
transimination procedure using NH2OH. Other derivatization reactions include the
transformation of azomethine imines into pyrazolones, and a kinetic resolution of the azomethine
imines by enantioselective reduction. The latter is crucial as it allows the synthesis of
enantioenriched βꢀamino carbonyls compounds from alkenes. Mechanistically, the direct
observation iminoꢀisocyanates was achieved by infrared spectroscopy under the reaction
conditions. To our knowledge, this is the first example of the observation of iminoꢀisocyanates
by IR. Finally, the nature of the transition state was explored experimentally and by DFT
calculations. These results provide support for a concerted, asynchronous transition state for the
aminocarbonylation event, a finding that is aligned with the observation of Markovnikov
products in reactions of unsymmetrical alkenes. Calculations on the potential energy surface
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support a reaction forming an iminoꢀisocyanate intermediate, requiring heating to undergo a
concerted aminocarbonylation, and a slightly exothermic overall process. In conclusion, this
work is a complete study on the generation and reactivity of rare amphoteric isocyanates, which
establishes their synthetic potential in the context of cycloaddition reactions. Efforts to develop
new reactivity of amphoteric reagents is ongoing, and will be reported in due course.
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EXPERIMENTAL SECTION
General Information. All commercially available materials were used without further
purification unless otherwise noted. Solvents for reactions were obtained from solvent system or
or dried over 4Å molecular sieves. Microwave reactions were performed using a Biotage
Initiator Eight microwave reactor and microwave vials. Reactions were monitored by analytical
thin layer chromatography (TLC), using glassꢀ or aluminumꢀbacked plates, cut to size. TLC
visualization was achieved by UV and stain (such as KMnO4, vanillin, ninhydrin). Flash column
chromatography was carried out using 40ꢀ63 ꢁm SiliCycle silica gel. H NMR and 13C NMR
1
spectra were recorded on 300 MHz and 400 MHz spectrometers at ambient temperature, except
where noted. Spectral data is reported in ppm using solvent as the reference. H NMR: CDCl3
1
(7.26 ppm), C6D6 (7.16 ppm), DMSOꢀd6 (2.50 ppm), tolueneꢀd8 (2.08 ppm), CD3OD (3.31 ppm).
13C NMR: CDCl3 (77.16 ppm), C6D6 (128.06 ppm), DMSOꢀd6 (39.52 ppm), CD3OD (49.00
ppm). 1H data was reported as: multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, appt = apparent triplet), coupling constants (J) in Hz, and integration. Infrared (IR)
spectra were obtained as thin films or as neat solids on FTIR instruments. High resolution mass
spectroscopy (HRMS) was performed by electron impact (EI) or QꢀTOF electrospray ionization
(ESI).
Hydrazones (1aꢀl) were synthesized according to known procedures.23,39 General procedures for
alkene aminocarbonylation and characterization data for new azomethine imines are provided.
Compounds 5aꢀg, 5j, 5r, 5u, 5v, 5x, 5ab, 5ac were previously reported.23,32a
Phenyl hydrazinecarboxylate. Hydrazine hydrate (30 mL, 50ꢀ60 wt% solution in H2O, 0.60
mol, 3 equiv) was diluted in CH2Cl2 (250 mL). A solution of diphenyl carbonate (43 g, 0.20 mol,
1 equiv) in CH2Cl2 (250 mL) was added dropꢀwise over 2 h while stirring at room temperature.
Immediately after the addition was complete, the mixture in concentrated in vacuo. The crude
product was isolated by column chromatography (gradient, 50% EtOAc and 50% hexanes to
100% EtOAc). Fractions contaminated with PhOH were recrystallized in CH2Cl2/Hexane. The
1
title compound was obtained as a white solid, 14.6 g (48% isolated yield). H NMR spectrum
was in agreement with the literature.23,48c
Phenyl 2ꢀ(9Hꢀfluorenꢀ9ꢀylidene)hydrazineꢀ1ꢀcarboxylate (4). Phenyl hydrazinecarboxylate
(2.43 g, 16.0 mmol), fluorenone (2.90 g, 16.0 mmol) and AcOH (0.20 mL) in MeOH (35 mL)
were heated to reflux for 6 h. The mixture was cooled to rt, and the product crystallized from
crude mixture. The product was obtained as yellow solid (4.0 g, 80% yield). m.p.: 178ꢀ180 °C.
TLC R
7.48 Hz, 1H), 7.82 (d, J = 7.63 Hz, 1H), 7.66 (d, J = 7.51 Hz, 1H), 7.56 (d, J = 7.43 Hz, 1H),
7.47ꢀ7.21 (m, 9H). 13C NMR (100 MHz, CDCl
) δ 152.1(C), 150.6 (C), 142.6 (C), 139.5 (C),
f
= 0.31 in 20% EtOAc/hexanes. 1H NMR (400 MHz, CDCl
3
) δ 9.18 (s, 1H), 7.91 (d, J =
3
136.8 (C), 131.4 (CH), 130.3 (CH), 129.7 (C), 129.6 (CH), 128.4 (CH), 128.1 (CH), 126.0 (CH),
125.6 (CH), 122.6 (CH), 121.5 (CH), 121.0 (CH), 119.7 (CH). ). IR (film) 1716, 1735, 1490,
1471, 1219, 1171, 772 cmꢀ1; HRMS (EI): Exact mass calcd for C20
Found: 314.1056.
H14
N2
O
[M]+: 314.1050.
2
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General Procedure A for the Intermolecular Aminocarbonylation of Alkenes (microwave
conditions).23,39 The hydrazone, the corresponding alkene (1 to 10 equiv) were added to an oven
or flame dried microwave vial with a stir bar. The mixture was diluted with α,α,αꢀ
trifluorotoluene (PhCF3, 0.5 to 0.05 M), unless noted otherwise (e.g. neat conditions or solvent
optimization). The vial was sealed with a septum and purged with argon. The mixture was heated
at the specified temperature in a microwave reactor for the given time. The reaction solution was
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cooled to ambient temperature, concentrated under reduced pressure and analyzed by H NMR
using 1,4ꢀdimethoxybenzene or 1,3,5ꢀtrimethoxybenzene as an internal standard. The
azomethine imine product was isolated using silica gel column chromatography.
General Procedure B for the Intermolecular Aminocarbonylation of Alkenes (reflux
23,39
conditions).
The hydrazone, the corresponding alkene (1 to 10 equiv) and α,α,αꢀ
trifluorotoluene (PhCF3, 0.5 to 0.05 M) were added to an oven or flame dried flask with a stir bar.
The flask was equipped with a reflux condenser and purged with argon. The mixture was heated
to 100 °C in an oil bath. The mixture was then cooled to ambient temperature, the stir bar
removed, and solvent was evaporated to give the crude product. The azomethine imine product
was isolated using silica gel column chromatography.
2ꢀ(9HꢀFluorenꢀ9ꢀylidene)ꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide
(5h).
Synthesized according to general procedure A using hydrazone 4 (0.157 g, 0.500 mmol) and 3ꢀ
methoxystyrene (0.35 mL, 2.5 mmol, 10 equiv) in PhCF3 (10 mL). The reaction was heated at
100 °C for six hours. The crude mixture was concentrated in vacuo, and the product isolated by
column chromatography (1:3 EtOAc/CH2Cl2 to remove excess alkene and byꢀproducts, then 20:1
MeOH/CH2Cl2 to elute the product). The product was obtained as a yellow solid (0.051 g, 29%
yield). TLC Rf = 0.24 in EtOAc. 1H NMR (300 MHz, CDCl3) δ 9.14 (d, J = 7.4 Hz, 1 H), 7.65 ꢀ
7.54 (m, 2 H), 7.50 ꢀ 7.34 (m, 3 H), 7.33 ꢀ 7.24 (m, 3 H), 7.12 ꢀ 7.03 (m, 1 H), 6.91 ꢀ 6.77 (m, 3
H), 6.30 (dd, J = 1.7, 9.4 Hz, 1 H), 3.74 (s, 3 H), 3.47 (dd, J = 9.4, 16.2 Hz, 1 H), 2.74 (dd, J =
2.0, 16.3 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 182.4, 160.6, 141.7, 141.2, 140.2, 139.4,
132.2, 131.7, 131.0, 130.9, 130.9, 129.4, 129.2, 128.0, 125.8, 120.8, 119.7, 116.8, 113.5, 110.8,
72.0, 55.3, 40.7. IR (ATR): 3071, 2982, 2939, 1658, 1605, 1550, 1274 cmꢀ1. HRMS (EI): Exact
mass calcd for C23H18N2O2 [M]+: 354.1368. Found: 354.1396.
2ꢀ(9HꢀFluorenꢀ9ꢀylidene)ꢀ3ꢀ(2ꢀmethoxyphenyl)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide
(5i).
Synthesized according to general procedure A using hydrazone 4 (0.157 g, 0.500 mmol) and 2ꢀ
methoxystyrene (0.34 mL, 2.5 mmol, 10 equiv) in PhCF3 (10 mL). The reaction was heated at
100 °C for six hours. The crude mixture was concentrated in vacuo, and the product isolated by
column chromatography (1:4 EtOAc/CH2Cl2 to remove excess alkene and byꢀproducts, then 9:1
EtOAc/MeOH to elute the product). The product was obtained as a yellow solid (0.128 g, 72%
1
yield). TLC Rf = 0.31 in EtOAc. H NMR (400 MHz, CDCl3) δ 9.12 (d, J = 7.3 Hz, 1 H), 7.53
(d, J = 7.5 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.45 ꢀ 7.32 (m, 2 H), 7.29 ꢀ 7.20 (m, 2 H), 7.17 (d,
J = 8.0 Hz, 1 H), 7.06 ꢀ 6.90 (m, 3 H), 6.83 ꢀ 6.72 (m, 1 H), 6.49 (dd, J = 2.0, 9.2 Hz, 1 H), 4.02
(s, 3 H), 3.43 (dd, J = 9.2, 16.6 Hz, 1 H), 2.57 (dd, J = 2.3, 16.6 Hz, 1 H). 13C NMR (100 MHz,
CDCl3) δ 183.1, 155.0, 141.5, 140.4, 140.1, 132.0, 131.6, 131.4, 130.7, 130.0, 129.5, 129.0,
127.9, 126.0, 125.3, 124.1, 121.8, 120.6, 119.6, 110.5, 67.6, 55.8, 39.4. IR (ATR): 3062, 2930,
2840, 1670, 1544 cmꢀ1. HRMS (EI): Exact mass calcd for C23H18N2O2 [M]+: 354.1368 Found:
354.1383.
2ꢀ(9HꢀFluorenꢀ9ꢀylidene)ꢀ5ꢀoxoꢀ3ꢀ(pꢀtolyl)pyrazolidinꢀ2ꢀiumꢀ1ꢀideide (5k). Synthesized
according to general procedure A using hydrazone 4 (0.159 g, 0.504 mmol) and 4ꢀmethylstyrene
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(0.66 mL, 5.0 mmol, 10 equiv) in PhCF3 (10 mL). The reaction was heated at 100 °C for three
hours. The crude mixture was concentrated in vacuo, and the product isolated by column
chromatography (1:1 Et2O/CH2Cl2 then 9:1 Et2O/MeOH to elute the product). The product was
1
obtained as a yellow solid (0.083 g, 48% yield). TLC Rf = 0.20 in EtOAc. H NMR (400 MHz,
CDCl3) δ 9.16 (d, J = 7.5 Hz, 1 H), 7.61 (dd, J = 4.1, 7.2 Hz, 2 H), 7.51 ꢀ 7.35 (m, 3 H), 7.34 ꢀ
7.28 (m, 1 H), 7.16 (s, 4 H), 7.12 ꢀ 7.03 (m, 1 H), 6.33 (dd, J = 1.5, 9.2 Hz, 1 H), 3.50 (dd, J =
9.3, 16.3 Hz, 1 H), 2.77 (dd, J = 1.8, 16.3 Hz, 1 H), 2.30 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ
182.7, 141.9, 141.5, 140.4, 138.8, 135.1, 132.4, 131.9, 131.8, 131.2, 130.5, 129.5, 129.4, 128.1,
126.2, 124.7, 120.9, 119.8, 72.2, 41.0, 21.2. IR (ATR): 3095, 1699, 1616, 1570, 1320 cmꢀ1.
HRMS (EI): Exact mass calcd for C23H18N2O [M]+: 338.1419 Found:338.1414
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3ꢀ(2ꢀBromophenyl)ꢀ2ꢀ(9Hꢀfluorenꢀ9ꢀylidene)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide (5l). Synthesized
according to general procedure A, using 4 (62.9 mg, 0.200 mmol), 1ꢀbromoꢀ2ꢀvinylbenzene
(0.13 mL, 1.0 mmol, 5 equiv) in PhCF3 (4.0 mL). The reaction was heated at 120°C for 3 hours.
The crude mixture was concentrated in vacuo, and the product isolated by column
chromatography (30% to 80% EtOAc/Hexanes, then 5% MeOH/EtOAc). The product was
1
obtained as a yellow solid (39.1 mg, 48% yield). TLC Rf = 0.08 (30% EtOAc/Hexanes). H
NMR (400 MHz, CDCl3) δ 9.14 (d, J = 7.4, 1H), 7.70ꢀ7.67 (m, 1H), 7.62ꢀ7.58 (m, 2H), 7.49ꢀ
7.46 (m, 1H), 7.41 (td, J = 1.2, 7.6 Hz, 1H), 7.30 (ddd, J = 2.0, 6.0, 7.7 Hz, 1H), 7.20 (dt, J = 3.0,
6.6 Hz, 2H), 7.12ꢀ7.06 (m, 3H), 6.51 (dd, J = 2.1, 9.3 Hz, 1H), 3.56 (dd, J = 9.3, 16.6 Hz, 1H),
2.67 (dd, J = 2.2, 16.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 182.3 (C), 142.1 (C), 141.4 (C),
140.6 (C), 137.3 (C), 133.7 (CH), 132.8 (CH), 132.1 (CH), 131.8 (C), 131.5 (CH), 130.8 (CH),
129.62 (CH), 129.57 (C), 129.47 (CH), 128.6 (CH), 125.74 (CH), 125.59 (CH), 121.8 (C), 121.2
(CH), 120.1 (CH), 72.5 (CH), 39.6 (CH2). IR (film) 1734, 1661, 1647, 1605, 1545, 1448, 1290,
1269, 1248 cmꢀ1. HRMS (EI): Exact mass calcd for C22H15BrN2O [M]+: 402.0368. Found:
402.0399.
3ꢀ(3ꢀBromophenyl)ꢀ2ꢀ(9Hꢀfluorenꢀ9ꢀylidene)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide
(5m).
Synthesized according to general procedure A, using 4 (62.9 mg, 0.200 mmol), 1ꢀbromoꢀ3ꢀ
vinylbenzene (0.18 g, 1.0 mmol, 5.0 equiv) in PhCF3 (4.0 mL). The reaction was heated at 120°C
for 3 hours. The crude mixture was concentrated in vacuo, and the product isolated by column
chromatography (30% to 50% EtOAc/Hexanes, then EtOAc, then 5% MeOH/EtOAc). Title
1
compound was obtained as a yellow solid (34.6 mg, 43% yield). TLC Rf = 0.48 (EtOAc). H
NMR (400 MHz, CDCl3): δ 9.10ꢀ9.08 (m, 1H), 7.58 (dd, J = 0.6, 7.4 Hz, 2H), 7.47ꢀ7.42 (m, 3H),
7.38 (td, J = 1.2, 7.6 Hz, 1H), 7.33ꢀ7.28 (m, 2H), 7.23ꢀ7.18 (m, 2H), 7.11ꢀ7.07 (m, 1H), 6.32 (dd,
J = 1,4, 9.3 Hz, 1H), 3.49 (dd, J = 9.4, 16.3 Hz, 1H), 2.72 (dd, J = 1.9, 16.3 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 182.3, 142.2, 141.9, 140.6, 140.4, 132.8, 132.4, 132.1, 131.84, 131.70,
131.64, 129.61, 129.46, 128.4, 128.1, 126.0, 124.2, 123.6, 121.3, 120.1, 71.7, 40.9. IR (film)
1653, 1607, 1549, 1450, 1342, 1275, 1246 cmꢀ1. HRMS (EI): Exact mass calcd for C22H15BrN2O
[M]+: 402.0368. Found: 402.0375.
2ꢀ(9HꢀFluorenꢀ9ꢀylidene)ꢀ5ꢀoxoꢀ3ꢀ(4ꢀ(trifluoromethyl)phenyl)pyrazolidinꢀ2ꢀiumꢀ1ꢀide (5n).
Synthesized according to general procedure A using hydrazone 4 (0.157 g, 0.500 mmol) and 4ꢀ
(trifluoromethyl)styrene (0.74 mL, 5.0 mmol, 10 equiv) in PhCF3 (10 mL). The reaction was
heated at 100 °C for six hours. The crude mixture was concentrated in vacuo, and the product
isolated by column chromatography (1:4 EtOAc/CH2Cl2 to remove excess alkene and byꢀ
products, then 9:1 EtOAc/MeOH to elute the product). The product was obtained as a yellow
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solid (0.045 g, 23% yield). TLC Rf = 0.17 in EtOAc. H NMR (400 MHz, CDCl3) δ 9.24 ꢀ 8.96
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(m, 1 H), 7.75 ꢀ 7.54 (m, 4 H), 7.53 ꢀ 7.36 (m, 4 H), 7.36 ꢀ 7.28 (m, 1 H), 7.26 (m, 1 H), 7.13 ꢀ
7.02 (m, 1 H), 6.46 (d, J = 8.4 Hz, 1 H), 3.57 (dd, J = 9.5, 16.4 Hz, 1 H), 2.74 (dd, J = 2.0, 16.4
Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 181.8, 141.8, 141.7, 141.4, 140.2, 132.5, 131.6, 131.4,
131.3, 131.0 (q, JCꢀF = 33.0 Hz), 129.2, 129.0, 128.0, 126.8 (q, JCꢀF = 3.7 Hz, 2C), 125.5, 125.3
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(2C), 123.5 (q, JCꢀF = 271 Hz), 121.0, 119.8, 71.4, 40.4. F NMR (377MHz, CDCl3) δ 62.8. IR
(ATR) 3095, 1992, 1733, 1695, 1623, 1577, 1456, 1372 cmꢀ1. HRMS (EI): Exact mass calcd for
C23H15F3N2O [M]+: 392.1136. Found: 392.1138.
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2ꢀ(9HꢀFluorenꢀ9ꢀylidene)ꢀ5ꢀoxoꢀ4ꢀ(4ꢀ(trifluoromethyl)phenyl)pyrazolidinꢀ2ꢀiumꢀ1ꢀide (6n).
Following same procedure as above for product 5n, the product 6n was also isolated as a yellow
solid (9.8 mg, 5% yield). TLC Rf = 0.49 in EtOAc. H NMR (400 MHz, CDCl3) δ 9.00 (d, J =
7.7 Hz, 1 H), 7.71 (d, J = 7.3 Hz, 1 H), 7.69 ꢀ 7.58 (m, 4 H), 7.55 ꢀ 7.43 (m, 4 H), 7.37 (ddd, J =
1.1, 7.7, 7.7 Hz, 1 H), 7.33 ꢀ 7.27 (m, 1 H), 5.38 (dd, J = 9.9, 13.5 Hz, 1 H), 4.86 (dd, J = 5.6,
13.5 Hz, 1 H), 4.37 (dd, J = 5.6, 9.9 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 183.5, 142.1,
142.0, 141.2, 140.3, 132.6, 131.7, 131.4, 131.2, 130.4, 130.3 (q, JCꢀF = 32.0 Hz), 129.4, 129.2,
128.5, 128.4, 126.4 (q, JCꢀF = 4.0 Hz, 2C), 125.7, 124.5, 124.1 (q, JCꢀF = 270 Hz), 121.5, 120.5,
120.1, 64.5, 47.5. IR (ATR) 3136, 1699, 1634, 1581, 1410, 1395 cmꢀ1. HRMS (EI): Exact mass
calcd for C23H15F3N2O [M]+: 392.1136. Found: 392.11375.
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2ꢀ(9HꢀFluorenꢀ9ꢀylidene)ꢀ3ꢀisobutylꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide
(5o).
Synthesized
according to general procedure A using hydrazone 4 (0.159 g, 0.506 mmol) and 4ꢀmethylꢀ1ꢀ
pentene (0.32 mL, 2.5 mmol, 5 equiv) in PhCF3 (5 mL). The reaction was heated by microwave
irradiation at 150 °C for 3 h. The crude mixture was concentrated in vacuo, and the product
isolated by column chromatography (1:3 EtOAc/CH2Cl2 to remove excess alkene and byꢀ
products, then 9:1 EtOAc/MeOH to elute the product). The product was obtained as a yellow
solid (0.069 g, 45% yield). TLC Rf = 0.23 in EtOAc. 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J =
7.6 Hz, 1 H), 7.71 (d, J = 7.0 Hz, 1 H), 7.62 (d, J = 7.5 Hz, 2 H), 7.48 ꢀ 7.39 (m, 2 H), 7.39 ꢀ 7.30
(m, 2 H), 5.51 ꢀ 5.30 (m, 1 H), 3.11 (dd, J = 8.2, 16.3 Hz, 1 H), 2.76 (d, J = 16.4 Hz, 1 H), 2.05 ꢀ
1.88 (m, 2 H), 1.87 ꢀ 1.77 (m, 1 H), 1.15 (d, J = 6.3 Hz, 3 H), 1.00 (d, J = 6.3 Hz, 3 H). 13C NMR
(101 MHz, CDCl3) δ 183.4, 142.2, 140.1, 140.0, 132.1, 132.0, 131.7, 131.2, 129.7, 129.4, 128.1,
125.5, 121.3, 119.8, 67.9, 42.8, 35.8, 26.1, 23.7, 21.5. IR (ATR) 3003, 2847, 1699, 1615, 1566,
1326 cmꢀ1. HRMS (EI): Exact mass calcd for C20H20N2O [M]+: 304.15756. Found: 304.15719.
3ꢀCyclohexylꢀ2ꢀ(9Hꢀfluorenꢀ9ꢀylidene)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide
(5p).
Synthesized
according to general procedure A using 4 (0.063 g, 0.20 mmol) and vinylcyclohexane (0.14 mL,
1.0 mmol, 5 equiv) in PhCF3 (4 mL). The reaction was heated by microwave irradiation at 120
°C for 3 h. The crude mixture was concentrated in vacuo, and the product isolated by column
chromatography (1:1 EtOAc/hexane, then 20:1 EtOAc/MeOH). The product was obtained as a
yellow solid (0.033 g, 50% yield). TLC Rf = 0.33 in EtOAc. 1H NMR (400 MHz, CDCl3) δ 9.06ꢀ
9.04 (m, 1H), 7.74ꢀ7.72 (m, 1H), 7.65 (d, J = 7.1, 1H), 7.47ꢀ7.43 (m, 3H), 7.36 (dtd, J = 1.3, 7.7,
9.0 Hz, 2H), 5.32ꢀ5.30 (m, 1H), 2.95 (dd, J = 8.9, 16.6 Hz, 1H), 2.73 (dd, J = 1.8, 16.6 Hz, 1H),
2.26ꢀ2.19 (m, 1H), 1.86 (t, J = 10.2, 2H), 1.75ꢀ1.66 (m, 2H), 1.55 (d, J = 12.6, 1H), 1.31ꢀ1.02
(m, 5H). 13C NMR (100 MHz, CDCl3) δ 184.0, 142.3, 139.9, 139.5, 132.09, 132.07, 131.7,
131.1, 130.2, 129.5, 128.6, 125.1, 121.4, 119.9, 72.8, 41.0, 32.4, 29.9, 26.3, 26.1, 25.6, 24.3. IR
(film) 2928, 2854, 1659, 1605, 1541, 1448, 1255 cmꢀ1. HRMS (EI): Exact mass calcd for
C22H22N2O [M]+: 330.1732. Found: 330.1734.
3ꢀ(tertꢀButyl)ꢀ2ꢀ(9Hꢀfluorenꢀ9ꢀylidene)ꢀ5ꢀoxopyrazolidinꢀ2ꢀiumꢀ1ꢀide
(5q).
Synthesized
according to general procedure A, using 4 (0.600 g, 1.91 mmol), 3,3ꢀdimethylbutꢀ1ꢀene (1.60 g,
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