Arynes double bond insertion/nucleophilic addition with vinylogous amides and carbodiimides

Article abstract of DOI:10.1021/jo402754d

Arynes are shown to insert into some C=X double bonds, leading to benzannulated four-membered rings. The strain of these rings allow for a ready, spontaneous opening to afford o-quinomethide analogues. Subsequent nucleophilic addition re-aromatizes the intermediates to achieve ortho-difunctionalization of arynes. In this report, we describe the aryne insertion into the C=C double bonds of vinylogous amides and the C=N double bonds of carbodiimides. The correlation and comparison with aryne single bond insertion chemistry will be discussed. Computational studies for the ring-opening step, as well as the nature of the o-quinomethide intermediates, will also be discussed.

Full text of DOI:10.1021/jo402754d

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Article
Arynes Double Bond Insertion/Nucleophilic Addition
with Vinylogous Amides and Carbodiimides
Ran Li, Huarong Tang, Haixing Fu, Hailong Ren, Xuemei Wang, Chunrui Wu, Chao Wu, and Feng Shi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo402754d • Publication Date (Web): 16 Jan 2014
Downloaded from http://pubs.acs.org on January 20, 2014
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Arynes Double Bond Insertion/Nucleophilic Addition with Vinylogous Amides and
Carbodiimides
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Ran Li,a,† Huarong Tang,b,c,† Haixing Fu,a Hailong Ren,a Xuemei Wang,a Chunrui Wu,*,a Chao Wu,*,d and Feng Shi,a
a Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus,
Kaifeng, Henan 475004, China PR
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b School of Materials Science and Engineering, Xi’an Jiaotong University
c State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University
d Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi 710054, China PR
† Equal Contributors
cwu@henu.edu.cn, chaowu@mail.xjtu.edu.cn, fshi@henu.edu.cn
Arynes are shown to insert into some C=X double bonds, leading to benzannulated four-membered rings. The strain of these
rings allow for a ready, spontaneous opening to afford ortho-quinomethide analogues. Subsequent nucleophilic addition
re-aromatizes the intermediates to achieve ortho-difunctionalization of arynes. In this report, we describe the aryne insertion
into the C=C of vinylogous amides and the C=N double bonds of carbodiimides. The correlation and comparison with aryne
single bond insertion chemistry will be discussed. Computational studies for the ring-opening step, as well as the nature of
the ortho-quinomethide intermediates will also be discussed.
Introduction
 Corresponding author. Tel.: +86-29-8339-5364; fax: +86-29-8339-5364; e-mail: chaowu@mail.xjtu.edu.cn
 Corresponding author. Tel.: +86-371-2286-4665; fax: +86-371-2286-4665; e-mail: cwu@henu.edu.cn, fshi@henu.edu.cn
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Arynes have been shown to insert into a number of single bonds.1 However, the corresponding aryne insertion into double
bonds are much less reported. This insertion involves first a [2+2] cycloaddition that affords a benzannulated four-membered
ring intermediate, which may exhibit different levels of instability and under the same or different reaction conditions may
undergo subsequent ring-opening processes to afford ortho-quinomethides (oQMs) or the analogues thereof (Scheme 1). The
two-step process furnishes a formal enyne metathesis outcome and generates another reactive intermediate, oQM, from an
existing one, aryne.
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Some double bonds that are known to undergo aryne insertion include the C=C bonds of enamides2 and enolates,3 the C=O
bonds of formamides4 and aldehydes,5 the C=N bonds of imines,6 and some miscellaneous double bonds.7 Depending on the
exact structure, the generated oQMs (or the analogues) may undergo a number of different subsequent processes to afford
stable final products, including 6 electrocyclization,5b,6b,7a [4+2] cycloaddition or annulation,2,5a,6a and nucleophilic addition
(Scheme 1).4a-c Very recently,
a
[4+1] annulations mode has also been disclosed.4d,8 Overall, either an
ortho-difunctionalization of arynes or formation of another ring is achieved.
Scheme 1. Aryne double bond insertion and the subsequent events
Despite this much discovery, to date, the aryne double bond insertion chemistry remains in its infancy and awaits further
study. For example, the mechanistic details for the [2+2] cycloaddition as well as the ring-opening have not been adequately
studied, and the dependency on the electronic properties and the atomic compositions of the double bonds remains unknown.
Moreover, the aryne insertion into the C=N bonds of imines and the C=C bonds of enolates was executed on diazotized
anthranilic acid, and is highly substrate-dependent and poorly yielding, thus necessitates further development. The insertion
into the C=O bonds of formamides requires the use of the latter as solvents under highly diluted conditions, thus poses scope,
economy, and workup issues. The insertion into the C=C bonds of enamides needs high temperature and is restricted to
certain substitution patterns. For this reason, continuing study is necessary to further broaden the substrate scope and to find
further utility of this event. Herein, we wish to continue from our communication9 and report our additional results in the
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carbodiimide system. Chemistry-wise, we are focusing our attention on the nucleophilic addition interception of the oQM
intermediates. We also wish to study some mechanistic details to enrich the understanding of these reactions.
Results and Discussions
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Insertion to C=C Double Bonds of Vinylogous Amides
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At the outset of our program, we wished to study the C=C double bond insertion. Given the electrophilic nature of arynes,
this insertion appeared reasonable only for electron-rich, nucleophilic C=C double bonds. As enamides have been previously
shown to undergo C=C double bond insertion,2 the analogous vinylogous amides appeared an ideal candidate, and were thus
chosen as the substrate for testing. The overall event is outlined in Scheme 2, which involves first a [2+2] cycloaddition
followed by a ring-opening to afford the ortho-quinodimethide (oQDM) intermediate 4, which may also have an iminium
inner salt resonance structure, followed by a nucleophilic attack by an alcohol to eventually afford 5 after hydrolytic workup.
Putatively, the push-pull nature of the olefin moiety in vinylogous amides would make the C=C double bond more polarized
and facilitate the initial aryne [2+2] cycloaddition, and the intermediate 4 was also believed to be much more stable and
easily generated than the counterpart derived from regular enamides. Both would help to achieve milder reaction conditions.
Scheme 2. Aryne insertion into vinylogous amides/nucleophilic addition/hydrolysis sequence
As the amino group was lost in the overall reaction, it can be varied for achieving a better yield or scope. Thus this amino
group was considered as part of the reaction “parameters” during the optimization of the reaction conditions (Table 1).
Aliphatic alcohols were ideal nucleophiles in the reaction because they are poorly reactive with arynes.10 We used methanol
for this purpose. As seen, the overall process worked best with slightly excess of methanol using CsF as the fluoride source in
acetonitrile at room temperature (entry 3). Mild heating to 50 ºC was tolerated with only a slight decrease in yield (not
shown). As for the amino group, both dibenzylamino and diisopropylamino were capable of delivering high yields of the
desired product (entries 3 and 6). The morpholino group afforded lower, but acceptable result (entry 7), but pyrolidinyl was
not a group of choice (entry 8).
Table 1. Optimization of the reaction of vinylogous amidesa
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entry
NR2 (1a)
MeOH/equiv
conditions
yieldb/%
39
1
2
NBn2 (1a-Bn)
NBn2
0c
0c
MeCN, rt, 36 h
THF, 70 ºC, 36 h
MeCN, rt, 24 h
MeCN, rt, 36 h
MeCN, rt, 20 h
MeCN, rt, 24 h
MeCN, rt, 24 h
MeCN, rt, 24 h
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28
3
NBn2
1.5
3
83
4
NBn2
52
5d
6
NBn2
1.5
1.5
1.5
1.5
<10
82
NiPr2 (1a-Pr)
morpholino (1a-mor)
pyrrolidinyl (1a-pyr)
7
66
8
23
a
Reactions were carried out on 0.3 mmol of 1a with 1.5 equiv of 2a and 3
b
c
equiv of CsF in 4.5 mL of solvent. Isolated yield. The reaction might be
proceeding with adventitious moisture. d TBAF (3 equiv) was used in place
of CsF.
Using this set of conditions, we next examined a diverse range of substrates with different substitutions and functionalities
(Table 2). However, we quickly realized that the dibenzylamino-substituted vinylogous amides (1-Bn) afforded poor results
for -substituted substrates. This prompted us to go back and re-examine the amino group. Luckily, the morpholino variants
(1-mor) were found to show broader compatibility (entries 1 and 3) with these substituted substrates. Thus, further studies
were executed on the corresponding 1-mor substrates. The scope of vinylogous amides was reasonable. In terms of the
-substitution (R), hydrogen and aryl groups were generally compatible. Aliphatic groups such as a methyl worked but were
less productive (entries 1 vs 2, 4 vs 5). Within the scope of substituted phenyl groups, either a strong electron-donating or a
strong electron-withdrawing group was tolerated, although the desired products were delivered in a lowered yield (entries 10
and 11, also compare with entry 2). A thiophenyl group was also well tolerated (entry 12). Regarding to the
electron-withdrawing group (EWG), ester (entries 1–2), ketone (entries 3–5), and cyano (entry 8) groups were all compatible.
Again, for different ketone groups as the EWG, aromatic ketones appeared superior to aliphatic ones (entries 3 vs 4). The
reactivity of amides as the EWG was reasonable for tertiary amides only (entry 7), and 1g-mor with a secondary amide (with
an NH bond) reacted only modestly (entry 6). Unfortunately, to date, we were unable to prepare substrates with R being a
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tert-butyl group, or substrates bearing -substitutions. The only one we could access was 1j-mor (entry 9), which did not
lead to any meaningful products.
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Table 2. Scope of the reaction of vinylogous amides with arynesa
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yieldb
/%
yield
b /%
entry
product
entry
product
1
2
2
1
2
31
1
9
CMc
2a
(CMc)
5ba
1b-mor
1c-mor
1d-mor
1j-mor
5ja
2
3
81d
10
11
55
2a
2a
5ca
5ka
1k-mor
23e
50
2a
2a
(trace)
5da
5la
1l-mor
4
5
49d
12
13
83
2a
2a
2a
2a
5ea
5fa
1e-mor
1f-mor
5ma
1m-mor
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22f
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1n-mor
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2a
2a
1a-mor
1a-mor
2c
5ac
5ad
1h-mor
1i-mor
5ha
5ia
2d
a
b
Reactions were performed with 0.3 mmol of 1 in 4.5 mL of MeCN. Reactions may not be individually optimized. Isolated yield.
c
Yields in parentheses were obtained from the corresponding 1-Bn substrates (dibenzylamino group in place of morpholino group).
Complex mixture. d Reaction took 12 h. e Reaction took 6 h. f Reaction took 36 h.
Two special cases were worth highlighting. Substrate 1n-mor with the vinylogous amide embedded into a ring did not lead
to any C=C insertion event. Rather, it underwent a -arylation11 to afford product 6 in a low yield (entry 13). Here the [2+2]
event did not seem to happen and the nucleophile did not participate in the reaction. The vinylogous amide 1o-mor, derived
from acetylenedicarboxylate and with R being another EWG, underwent a formal C–C single bond insertion to afford 7
(Scheme 3). In this case, the [2+2] event can be viewed to occur to the undesired “C=C double bond” (the enolate double
bond if one draws the polar resonance structure of 1o-mor) and again the nucleophile did not participate in the reaction.
Scheme 3. Formation of 7 from 1o-mor and the proposed mechanism. The Z-geometry is assigned by NOE (see the SI)
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The scope of arynes included both the symmetrical 2d and the unsymmetrical 2b/2c. For the latter, the regioselectivity was
in accordance with the traditional electronic rationale,1b i.e. the nucleophilic site of the vinylogous amides attacking the distal
position of the methoxy-substituted arynes (entries 14–15). The yields were satisfactory and comparable to that for 5aa.
Insertion to C=N Double Bonds of Carbodiimides
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Having achieved the C=C bond insertion of vinylogous amide, we next turned our attention to the C=N bond insertion.
Although arynes are known to insert into the C=N bonds of some imines,6 such a reaction does not work well as indicated
both in our own experiences and from Yoshida’s report.12 We reasoned that the carbon atom of the imine might be
insufficiently electrophilic for the aryl anion to cyclize back to achieve the initial [2+2] cycloaddition, despite that the imine
nitrogen is sufficiently nucleophilic to arynes. Thus, a proper substrate with increased electrophilicity was sought.
Carbodiimides possess C=N double bonds with much more electrophilic carbon atoms and appeared an ideal candidate in
such a scenario. Putatively, the aryne insertion of C=N double bonds of carbodiimides would feature an
aza-ortho-quinomethide (aoQM) intermediate 10, which can be easily quenched by alcohols or water to afford the
amide/imidate products 11. Depending on the stoichiometry and the reaction conditions, 11 might react with a second
equivalent of aryne to afford 12 as the final product (Scheme 4, pathway A). That said, one should keep in mind that
carbodiimides may first react with the alcohol (not arynes) to afford carbamimidate intermediates (Scheme 4, pathway B, first
step). However, we envisioned that even if this was happening, this carbamimidate would still afford a same product 11 or 12
following the mechanism described in pathway B. Computational studies support pathway A as the preferred mechanism (see
the Supporting Information).
Scheme 4. The three-component reaction of aryne, carbodiimides, and a nucleophile
Again, we commenced at optimizing the reaction conditions (Table 3). Here we used water as the nucleophile and
expected an amide functionality at the end of the reaction. The reaction required elevated temperature and afforded good
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yields only at 80 ºC in acetonitrile (entry 4). Stopping at the stage of 11 proved difficult, and a continuing arylation was
taking place. Of note is that this continuing N-arylation took place only at the amine nitrogen, but not the amide nitrogen.
Table 3. Optimization of the reaction of carbodiimidesa
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entry
H2O/equiv
conditions
yieldb/%
35
1
2
1.2
1.2
1.2
1.2
1.2
3
THF, 70 ºC, 24 h
MeCN, rt, 24 h
MeCN, 50 ºC, 10 h
MeCN, 80 ºC, 5 h
MeCN, 90 ºC, 5 h
MeCN, 80 ºC, 5 h
THF, rt, 12 h
37
3
55
4
77
5
63
6
25
7c
1.2
40
a Reactions were carried out on 0.15 mmol of 8a, 0.2 mmol of 2a, and 0.25
mmol of CsF in 2 mL of solvent. Compound 2a was the limiting agent. One
b
c
equiv of H2O = 0.1 mmol. Isolated yield. Reaction was performed with
18-crown-6 (2 equiv).
Different nucleophiles and carbodiimides were then examined (Table 4). Under the standard conditions, MeOH, EtOH,
i
and PrOH were all successfully employed as the nucleophile. Different from the amide products derived from the reaction
using water, these reactions using alcohols afforded the corresponding imidates (entries 2–4). Again, the less nucleophilic
tBuOH proved incompatible as a nucleophile (entry 5), and formation of 12ba-H was observed likely due to the involvement
of adventitious moisture. Use of ethylene glycol as the nucleophile led to a hydrolysis of the imidate moiety to afford the
ester functionality (entry 6).13 Other than alcohols, N-hydroxylamines such as N-hydroxylphthalimide proved not effective
(entry 7). For nitrogen nucleophiles, hydantoin and succinimide (entry 8) were both reactive. Yet unfortunately we were
unable to purify the former product.14 Interestingly, use of both ethylene glycol and succinimide as the nucleophile led to two
products 11 and 12, where the subsequent N-phenylation was somewhat suppressed.15
In terms of carbodiimides, the commercially available dicyclohexyl and di-iso-propyl ones worked well under our
conditions. More sterically hindered di-tert-butylcarbodiimide afforded a lower yield (entry 9). Carbodiimides with two small
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primary alkyl groups, such as methyl or ethyl, are highly unstable and were not examined.16 Those with aromatic groups
exhibited very low reactivity at 80 ºC and led to complex mixtures upon further heating.14 Although we did not anticipate a
good regioselectivity in the C=N bond insertion step for unbiased unsymmetrical carbodiimides, substrate 8d bearing a
tertiary and a primary alkyl groups afforded a complete regioselectivity with the C=N insertion taking place on the less
hindered site (entry 10). N-Alkyl-N’-arylcarbodiimides tested were either unstable or did not afford the desired products (not
shown). A few arynes were also examined. The biased 3-methoxybenzyne derived from 2b resulted in a complete
regioselectivity (entry 11). This time, the less biased 4-methoxybenzyne derived from 2c afforded a mixture of all four
possible regioisomers (entry 12). The reaction with 2d was uneventful despite a modest yield (entry 13).
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Table 4. Scope of the reaction of carbodiimides with arynesa
entry
HNu
H2O
product
yieldb/%
8
2
1
71
2a
8b
8b
12ba-H
12ba-Me
12ba-Et
2
MeOH
81c
2a
3
4
EtOH
69c
8b
8b
2a
2a
iPrOH
64c
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12ba-Pr
1
2
3
4
5
6
7
8
9
5
6
7
tBuOH
- (56)
8b
8b
8b
2a
2a
2a
10
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12
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12ba-Bu
ethylene
glycol
57d
12ba-G
- (29)
12ba-Phth
8
37e
8b
2a
12ba-Su
12ca-H
12da-H
9
H2O
35
2a
8c
10
H2O
41
2a
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8b
11
H2O
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7
8
9
12
H2O
76f
8b
2c
10
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12bc-H
13
H2O
43
8b
2d
12bd-H
14
MeOH
38
2a
13
14
a
Reactions were performed with 0.3 mmol of 8 in 4 mL of MeCN. Aryne was the limiting agent. 1
b
equiv = 0.2 mmol. Isolated yield. Yields in parentheses refer to the corresponding amide products
c
d
obtained by moisture intrusion. Using 2.4 equiv of alcohol. The corresponding 11ba-G product
e
(without the N-phenylation) was also isolated in ~18% yield. The corresponding 11ba-Su product
(without the N-phenylation) was also isolated in ~12% yield. f Containing four inseparable regioisomers;
see the Experimental Section for detail.
Before we conclude this section, it should be additionally noted that Hsieh and co-workers have previously reported that
isocyanates, which are isoelectronic to carbodiimides, react with arynes in a completely different mechanism and outcome.17
The nitrogen atom of isocyanate is sufficiently nucleophilic to aryne, but the [2+2] cycloaddition did not occur (vide infra, cf.
Scheme 5a). Since our reaction conditions are slightly different from Hsieh’s (no lutidine, different stoichiometry, and use of
MeOH in place of water), we attempted to employ 4-chlorophenylisocyanate 13 (entry 14) under our reaction conditions to
see if it could lead to a successful [2+2] cycloaddition. To our disappointment, product 14 was isolated in 38% yield coming
from Hsieh’s chemistry and no product 11 or 12 was obtained. Such results showcase another example that isoelectronic
replacement of atoms in substrates for aryne chemistry can result in significantly altered mechanism and final product.
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Scheme 5a illustrates the contrasted mechanisms for isocyanates and carbodiimides. As the direct [2+2] cycloaddtion is
forbidden in both cases by the Woodward-Hoffmann rule, the real reactions should take a stepwise mechanism by bonding
N(isocynate/carbodiimide)–C(benzyne) first leading to species 15, then closing the C–C bond afterwards. A brief Intrinsic
Reaction Coordinate calculation (IRC, electronic energies) has shown that species 15 are not stationary points, and lie on a
fairly flat plateau (see the Supporting Information for details). The energetic profile for the transition from 8/13 to 15A/15B
comes with a big difference: it takes 10.5 kcal/mol (Gibbs free energies, B3LYP/6-31++(d,p) level, using
dimethylcarbodiimide as the substrate, solvation effect considered) to convert 8 to 15A, but 20.6 kcal/mol (Gibbs free
energies, B3LYP/6-31++(d,p) level, using methyl isocyanate as the substrate, solvation effect considered) to convert 13 to
15B. This difference is in agreement with a decrease in the negative charges on the X atoms during the [2+2] cycloaddition
step (see the Supporting Information for details), which might partially account for the latter reaction coming with a higher
energy barrier (as it is energy-costing for an oxygen atom to suffer from substantial decrease in negative charge). It is also
probably why in Hsieh’s chemistry, lutidine has to be employed so as to generate a much more nucleophilic anionic species
to attack aryne.
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Another difference lies in the reactivity of species 15, which remains not well understood to us. For 15A derived from
carbodiimides (X = NR), the aryl anion prefers to cyclize to the central sp-carbon and leads to 9, thus finishing the [2+2]
event, whereas for 15B derived from isocyanates, water (or methanol) reacts with it leading to a quick protonation of the aryl
anion and the spontaneous formation of carbamate 14. Although a clear explanation is still lacking, calculation shows that
15B from isocyanate features a more negatively charged (Mulliken) aryl anion which could be more easily protonated (or
quenched by other electrophiles). But for sure, other unclear factors are also in play to account for this difference in
reactivity.
Scheme 5. The difference between carbodiimides and isocyanates
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The Ring-Opening Step and the Nature of the QM Intermediate
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As mentioned before (cf. Scheme 1), the aryne insertion of C=X bonds is the net result of two steps, an initial [2+2]
cycloaddition and a subsequent ring opening. The latter step may have two distinctly different mechanistic concerns.
Reported by Oppolzer,18 the ring opening of benzannulated four-membered rings was found to be highly dependent upon the
exocyclic substituents on the four-membered ring: the more electron-rich the exocyclic atoms are, the easier the rings would
open. This is in high agreement with the possibility that the -electrons of the exocyclic substitution are involved in the
ring-opening process, as described in Scheme 6, pathway C. In this mechanism, both the ring-opening process from 3 to 4
(for vinylogous amides) and that from 9 to 10 (for carbodiimides) can be considered as a lone-pair-assisted, strain-driven ring
opening that leads to inner-salt-typed intermediates 4-IS and 10-IS, where the aromaticity of the benzene ring remains intact.
A second possibility is the classical retro-4 electrocyclization process which to some extent breaks the aromaticity of the
benzene ring and leads to a classical ortho-quinomethide intermediates 4-QM and 10-QM (Scheme 6, path D). Although we
believed that these two pathways should be considered as two extremes and the real events should be hybrids of the two, we
were still interested to look into these mechanistic details, in hope to shed light on future reaction design and development.
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Scheme 6. Two mechanism extremes for the ring-opening step
We first studied the ring-opening process from 3 to 4 at the B3LYP/6-31++(d,p) level, using a simplified system of methyl
3-(dimethylamino)acrylate. According to Figure 1, it can be seen that structure 3 features a benzene ring with a significant
level of bond length averaging, except that the right side of the benzene ring is slightly compressed. The harmonic oscillator
model of aromaticity (HOMA) index19 for this benzene ring is 0.965, close to unity for an ideal benzene. Since 4-IS and
4-QM are two resonance structures representing the same chemical entity, the ring-opening from 3 to 4 should experience a
single transition state TS3-4 (not one for 4-IS and another for 4-QM), which can be located along the reaction coordinate (Fig.
1, intrinsic reaction coordinate analysis can be found in the Supporting Information). From 3 to 4, the three shorter bonds on
the right side of the benzene ring (C2–C3, C3–C4, and C4–C5) were considerably lengthened, and the C11–C12 bond was
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broken. At the same time, the C1–C2 and C5–C6 bonds were significantly shortened. For structure 4, the C1–C2 and C5–C6
bonds have more double bond character and the rest four on the benzene ring have more single bond character. In particular,
the C3–C4 bond is the longest and closest to a single bond, arguing against an aromatized structure in 4-IS. The HOMA
index for the benzene ring in 4 is only 0.284, suggesting a big loss of aromaticity, another piece of clear evidence that 4 has a
significant quinomethide (4-QM) character. Moreover, the Natural Bond Orbital (NBO) charges of N14 and C12 in structure
4 are -0.43 and -0.41, respectively. This further disfavors the inner salt (IS) structure, which should have positive charge on
N14. Further NBO calculation for structure 4 reveals a lone pair on N14 (Fig. 1b), contrary to the 4-IS structure. All these
results support 4 as mainly an oQM and the ring-opening of 3 is featured mainly with a retro-4 electrocyclic process. That
said, the C5-C4-C11-N14 dihedral angle in TS3-4 was 50 º, suggesting not to rule out a weak interaction of the N14 lone pair
with the C11–C12 * orbital in the transition state (the ideal dihedral angle for path C should be 90 º).
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Figure 1. The ring-opening mechanism of vinylogous amides in acetonitrile (Bond lengths are in Å and NBO charges are in red.
Gibbs free energies are reported here). Insets (a) Atom numbering. (b) The lone pair NBO orbital on nitrogen in 4.
Next, the same step from 9 to 10 was calculated, again using a simplified system of dimethylcarbodiimide. As shown in
Figure 2, structure 9 also features a benzene ring with a significant level of bond length averaging, but less than the extent for
3. Here, the C1–C2, C3–C4, and C5–C6 bonds are shorter than the other three. The HOMA aromaticity index for this
benzene ring is 0.926, less than that for 3 but again close to unity for an ideal benzene. From 9 to 10, it is very clear that the
C2–C3 bond is considerably lengthened with the separation of C12–N11. Once again, the resultant structure 10 features more
double bond character for C4–C5 and C1–C6, and more single bond character for the rest four bonds, in particular C2–C3.
These results are again consistent to the classical view of an aza-quinomethide (10-QM) structure but not the inner salt
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(10-IS). The HOMA aromaticity index for the benzene ring of 10 is 0.007, indicative of a complete loss of aromaticity. The
NBO charges of the two nitrogen atoms in 10 are -0.38 and -0.51, respectively, arguing against a positively charged N17
atom in the structure of 10-IS. Further calculation for 10 also reveals a lone pair at N17 (Fig. 2b), further suggesting the QM
structure. All these pieces of evidence, plus a less aromatized structure of 10 compared to that of 4, are in agreement of 10 as
mainly an aoQM. In turn, they also support that the process from 9 to 10 being a retro-4 electrocyclic event. Here the
dihedral angle of C4-C3-C12-N17 in TS9-10 is small (21 º, the ideal dihedral angle for path C should be 0 º), again suggesting
not to rule out the interaction of N17 lone pair and the C12–N11 * orbital in path C. But considering that they are not in
parallel, their interaction should not be very strong even if they are co-planar.
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Figure 2. The ring-opening mechanism of 9 in acetonitrile (Bond length are in Å and NBO charges are in red. Gibbs free
energies are reported here). Insets (a) Atom numbering. (b) The lone pair NBO orbital on nitrogen in 10.
The energy profiles illustrated in Fig. 1 and Fig. 2 can be correlated to the Bell-Evans-Polanyi principle: for two similar
processes, the higher the activation energy, the less exothermic the reaction is. Thus, the shift from a slight exothermic
reaction from 3 to 4 to a slight endothermic reaction from 9 to 10 is well correlated to the much higher activation energy of
the latter process, which can be partly linked to the extent of the aromaticity loss according to our calculation.
Correlation to Aryne Single Bond Insertion
Although the two reactions described in this report feature a different mechanism, synthetic chemists would easily wish to
compare these reactions to the previously reported aryne insertion into single bonds. For example, the reaction with
vinylogous amides appears similar to, at least in the perspective of product formation, the aryne C–C single bond insertion
reaction with active methylene compounds (Scheme 7).20 Indeed, compounds 5ba, 5ca, 5da, 5fa, and 5ia (cf. Table 2) can all
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be prepared from the corresponding 1,3-diketones, 3-ketoesters, or 3-ketonitriles according to literature reports. Since some
vinylogous amides, including 1b-mor, 1d-mor, and 1e-mor used in our hand, can be prepared from these dicarbonyl
compounds, detouring via the intermediacy of vinylogous amides might not seem chemically sound from a synthetic point of
view. However, in a more broad perspective, one should keep in mind that aryne C–C single bond insertion does not come up
with a substrate scope broad enough to cover every type of active methylene compound. For instance, to date, arynes have
not been known to insert into the C–C single bonds of 3-ketoamides,21 and therefore compounds 5ga and 5ha are inaccessible
through such chemistry. The scope of 1,3-diketones has not yet been able to cover unsymmetrical substrates, and therefore
formation of compound 5ea with high regioselectivity would imaginably be an issue. For both 1,3-diketones or 3-ketoesters,
the known aryne insertion does not yet cover aldehydic substrates, and therefore formation of compound 5aa would also be
questionable. On the other hand, the difficulty in preparing -substituted vinylogous amides and the different reactivity of
cyclic vinylogous amides (such as 1n-mor) make the C–C single bond insertion of active methylene compounds more
attractive for those particular products. For these reasons, the aryne C=C double bond insertion developed by us and the
aryne C–C single bond insertion developed by Stoltz and Yoshida are complementary. Even more so, the vinylogous amides
can be prepared more easily from a Michael addition of morpholine to alkynes equipped with EWGs, making a wider scope
of substrates accessible.
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Scheme 7. Comparison of aryne insertion chemistry with vinylogous amides and 1,3-dicarbonyl compounds
Similarly, the reaction with carbodiimides would be compared with, at least in the perspective of product formation, the
aryne C–N single bond insertion with ureas (Scheme 8).22 Again, as the carbodiimides are prepared from the corresponding
ureas, going through the carbodiimides would also appear as a detour. However, careful comparison with the literature
conditions and scopes reveals that these two events are even less alike. For one thing, the urea insertion reaction has to be
carried out using the urea as a solvent, thus posing economy and purification problems. The substrate scope of the urea
insertion23 was also limited to those ureas bearing no free NH bonds, primary alkyl groups as R, and only methyls as R’; and
the sole unsymmetrical urea reported in literature afforded very low yield. Thus at least in these aspects, the carbodiimide
chemistry does not have these drawbacks. Interestingly, the urea chemistry and the carbodiimide chemistry offer
complementary scopes of substrates: the former is best for substrates bearing small, primary R/R’ groups, while the latter is
best for those with branched R groups. In addition, the urea insertion could only afford amide products, and access to
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imidates or amidines remains out of the question. It is yet unfortunate that some carbodiimides are difficult to access and the
arylcarbodiimides do not react well.
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Scheme 8. Comparison of aryne insertion chemistry with carbodiimides and ureas
Conclusions
In summary, arynes were found to insert into the C=C double bonds of vinylogous amides and the C=N double bonds of
carbodiimides. These insertion reactions furnish unstable ortho-quinomethide-typed intermediates, which are confirmed
favorable over inner-salt structures by computational studies. These oQMs were demonstrated to be intercepted by various
nucleophiles to achieve a net ortho-difunctionalization of arynes.
Experimental Section
Solvents THF and MeCN were distilled from Na/benzophenone and CaH2, respectively. The silica gel for column
chromatography was supplied as 300–400 mesh, and basic alumina for column chromatography (pre-activated) was supplied
as 200–300 mesh. Powdered CsF was used as received and stored in a desiccator. Anhydrous alcohols were dried over 4 Å
molecular sieves before use. All aryne reactions were carried out in oven-dried glassware and were magnetically stirred. A
closed system was used but no efforts were made to exclude air.
1
All melting points are uncorrected. The H and 13C NMR spectra are referenced to the residual solvent signals (7.26 ppm
1
1
for H and 77.0 ppm for 13C in CDCl3, or 2.05 ppm for H and 29.8 ppm for 13C in acetone-d6). The HRMS spectra are
recorded using a Fourier-transformed ion cyclotron resonance analyzer.
All compounds in Table 2, with the exception of 1b-Bn, 1d-Bn, 1d-mor, 1g-mor, 1j-mor, 5da, and 5ga, have been
reported in our previous communication9 and are adequately characterized. Aryne precursors, carbodiimides, and isocyanate
13 are commercially available and were used as received. The rest is listed here.
Preparation of vinylogous amides (1b-Bn, 1d-Bn, 1d-mor, 1g-mor, 1j-mor, and 1o-mor):
Ethyl 3-(dibenzylamino)but-2-enoate (1b-Bn): to a mixture of 22 mg of Zn(OAc)2·2H2O (0.1 mmol, 5 mol %) and 260 mg
of ethyl acetoacetate (2 mmol) was added 0.58 mL of dibenzylamine (3 mmol, 1.5 equiv) under N2. The mixture (neat) was
stirred at 50 C for 12 h. The product was recrystallized from petroleum ether. It was collected via suction filtration to afford
457 mg of 1b-Bn (74%) as a white solid; mp 110–111 ºC. 1H NMR (400 MHz, CDCl3): 
7.35 (apparent t, J = 7.3 Hz, 4
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H), 7.29 (apparent d, J = 7.2 Hz, 2 H), 7.14 (apparent d, J = 7.1 Hz, 4 H), 4.86 (s, 1 H), 4.52 (s, 4 H), 4.07 (q, J = 7.1 Hz, 2
H), 2.61 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
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4-(Dibenzylamino)pent-3-en-2-one (1d-Bn): the above procedure was applied to 110 mg of Zn(OAc)2·2H2O (0.5 mmol, 5
mol %), 1.03 mL of acetoacetone (10 mmol), and 2.9 mL of dibenzylamine (15 mmol) for 48 h. The product was purified by
silica gel column chromatography eluting with 4:1 petroleum ether/EtOAc (with 1.5 vol % Et3N) to afford 1.12 g of
1d-Bn (40%) as a light yellow solid (the small quantity of contaminating dibenzylamine can be removed by washing with
cold petroleum ether); mp 166–167 ºC. 1H NMR (400 MHz, CDCl3): 7.37 (apparent t, J = 8.2 Hz, 4 H), 7.31–7.28 (m, 2
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H), 7.14 (apparent d, J = 7.1 Hz, 4 H), 5.33 (s, 1 H), 4.54 (s, 4 H), 2.66 (s, 3 H), 2.02 (s, 3 H)
4-Morpholinopent-3-en-2-one (1d-mor): the above procedure was applied to 55 mg of Zn(OAc)2·2H2O (0.25 mmol, 5 mol
%), 500 mg of acetoacetone (5 mmol), and 435 L of morpholine (5 mmol) to afford 540 mg of 1d-mor (64%) as a white
solid (crystallized from petroleum ether at -10 C); mp 44–45 ºC (lit.24 45–47 ºC). 1H NMR (400 MHz, CDCl3):  5.23 (s, 1
H), 3.72 (apparent t, J = 5.0 Hz, 4 H), 3.30 (apparent t, J = 5.0 Hz, 4 H), 2.47 (s, 3 H), 2.09 (s, 3H).
N-(p-Tolyl)-3-morpholinobut-2-enamide (1g-mor): to a solution containing 9.5 mg of TsOH·H2O (0.05 mmol, 5 mol %)
and 191 mg of N-(p-tolyl)-3-oxobutanamide25 (1 mmol) in 5 mL of benzene was added 131 L of morpholine (1.5 mmol).
The mixture was stirred at 80 C for 12 h. The product was recrystallized from benzene to afford 148 mg of 1g-mor (57%) as
1
a white solid; mp 181–182 ºC. H NMR (400 MHz, acetone-d6):  8.59 (s, 1 H), 7.54 (d, J = 8.2 Hz, 2 H), 7.03 (d, J = 8.1
Hz, 2 H), 5.04 (s, 1 H), 3.66 (apparent t, J = 4.6 Hz, 4 H), 3.13 (apparent t, J = 4.6 Hz, 4 H), 2.45 (s, 3 H), 2.24 (s, 3 H); 13
C
NMR (100 MHz, acetone-d6):  167.3, 159.5, 139.3, 131.8, 129.7, 119.5, 93.8, 66.9, 47.4, 20.7, 15.1; HRMS (ESI): calcd for
C15H21N2O2+ [M+H]+ 261.1598, found 261.1595.
2-(Morpholinomethylene)malononitrile (1j-mor): to a solution of 610 mg of ethoxymethylenemalononitrile26 (5 mmol) in 5
mL of DCM at 0°C was added a solution of morpholine (457 L, 5.25 mmol in 2.8 mL of THF) dropwise over 15 min. The
mixture was then allowed to warm to room temperature and stirred for 1 h. The volatiles were evaporated and the product
was crystallized from EtOAc to afford 594 mg of 1j-mor (73%) as a white solid; mp 148–149 ºC (lit.27 148–149 ºC). H
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NMR (400 MHz, CDCl3):  7.02 (s, 1 H), 3.96 (br, 2 H), 3.81–3.78 (m, 4 H), 3.49 (br, 2 H).
Diethyl 2-morpholinomaleate (1o-mor): to a solution of 209 mg of morpholine (2.4 mmol) in 7 mL of H2O was added 340
mg of diethyl acetylenedicarboxylate (2 mmol). The reaction mixture was stirred vigorously at room temperature for 2 h. The
product was extracted with ethyl acetate and the combined extracts were dried over Na2SO4, filtered, and concentrated. The
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residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to afford 461 mg of 1o-mor (90%) as
a yellow oil. 1H NMR (400 MHz, CDCl3):  4.79 (s, 1 H), 4.38 (q, J = 7.2 Hz, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 3.74 (apparent
t, J = 4.9 Hz, 4 H), 3.14 (apparent t, J = 4.9 Hz, 4 H), 1.37 (t, J = 7.2 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H). The 4.79 ppm signal
corresponds to the E-isomer.28
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Reaction of arynes with vinylogous amides (5da, 5ga, and 7):
1-(2-Acetylphenyl)acetone (5da): to an oven-dried 10 mL round-bottom flask equipped with a stirrer were added 134 mg of
aryne precursor 2a and 51 mg of 1d-mor. Dry MeCN (4.5 mL) was added, followed by 0.45 mmol of MeOH (18 L, reagent
grade). CsF (137 mg, 0.9 mmol) was added last, and the mixture was stirred at room temperature for 6 h. Upon completion,
the reaction mixture was poured into brine and extracted three times with EtOAc. The combined extracts were dried over
Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (7:1 petroleum
ether/EtOAc) to afford 12 mg of 5da (23%) as a slightly yellow glass (containing a trace of petroleum ether residue, not
affecting yield). 1H NMR (400 MHz, CDCl3): 7.85 (d, J = 7.7 Hz, 1 H), 7.48 (td, J = 7.5, 1.3 Hz, 1 H), 7.39 (td, J = 7.6, 1.2
Hz, 1 H), 7.18 (d, J = 7.5 Hz, 1 H), 4.03 (s, 2 H), 2.58 (s, 3 H), 2.29 (s, 3 H); 13C NMR (100 MHz, CDCl3): 205.7, 201.0,
136.5, 135.1, 132.9, 132.2, 130.2, 127.3, 49.4, 30.0, 28.6; HRMS (ESI): calcd for C11H13O2 [M+H]+ 177.0910, found
+
177.0907.
N-(p-tolyl)-2-(2-acetylphenyl)acetamide (5ga): the above procedure was applied to 78 mg of 1g-mor to afford 16 mg of
5ga (20%) as a white solid; mp 138–139 ºC. 1H NMR (400 MHz, CDCl3):  9.61 (brs, 1 H), 8.17 (dd, J = 7.8, 1.1 Hz, 1 H),
7.97 (d, J = 7.0 Hz, 1 H), 7.88 (td, J = 7.6, 1.2 Hz, 1 H), 7.79–7.73 (m, 3 H), 7.44 (d, J = 8.3 Hz, 2 H), 4.18 (s, 2 H), 3.08 (s,
3 H), 2.65 (s, 3 H); 13C NMR (100 MHz, CDCl3): 203.9, 168.7, 137.1, 135.9, 135.3, 133.2, 132.7, 132.4, 129.9, 129.3,
127.2, 119.4, 43.1, 29.4, 20.8; HRMS (ESI): calcd for C17H17NNaO2+ [M+Na]+ 290.1152, found 290.1152.
Ethyl 2-(3-ethoxy-2-morpholino-3-oxoprop-1-en-1-yl)benzoate (7): the above procedure was applied to 77 mg of 1o-mor
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to afford 60 mg of 7 (60%) as a yellow oil. H NMR (400 MHz, CDCl3):  7.40–7.36 (m, 1 H), 7.18 (dd, J = 8.0, 1.6 Hz, 1
H), 7.13–7.09 (m, 2 H), 6.75 (s, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 4.08 (q, J = 7.1 Hz, 2 H), 3.71 (br, 4 H), 2.88 (br, 4 H), 1.24
(t, J = 7.1 Hz, 3 H), 1.11 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 167.7, 165.7, 150.9, 145.6, 131.5, 130.8, 130.1,
126.8, 123.7, 119.4, 67.1, 61.4, 60.7, 52.2, 14.2, 13.8; HRMS (ESI): calcd for C18H24NO5 [M+H]+ 334.1649, found
+
334.1647. A weak NOE correlation was observed: 7.1 to 2.88.
Reaction of arynes with carbodiimides (12):
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Representative procedure (outlined for 12aa-H, N-cyclohexyl-2-(cyclohexyl(phenyl)amino)benzamide in the conditions
shown in entry 5, Table 3): to an oven-dried 8 mL vial equipped with a stirrer were added 59.6 mg of 2a (0.2 mmol) and 30.9
mg of DCC (0.15 mmol). Dry MeCN (2 mL) was added, followed by 2.2 L of H2O (0.12 mmol). CsF (38 mg, 0.25 mmol)
was added last and the mixture was stirred at 80°C for 5 h. Upon completion, the reaction mixture was poured into brine and
extracted three times with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue
was purified by silica gel column chromatography (9:1 petroleum ether/EtOAc) to afford 28.8 mg of 12aa-H (77%) as a
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slightly yellow solid; mp 83–84°C. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 6.8 Hz, 1 H), 7.59 (br, d, J = 6.8 Hz, 1 H),
7.50–7.41 (m, 2 H), 7.19 (t, J = 7.9 Hz, 2 H), 7.09 (d, J = 7.5 Hz, 1 H), 6.77 (t, J = 7.2 Hz, 1 H), 6.58 (d, J = 8.2 Hz, 2 H),
3.91–3.76 (m, 2 H), 2.08–2.02 (m, 2 H), 1.80–1.60 (m, 5 H), 1.46–1.24 (m, 7 H), 1.13–0.86 (m, 6 H); 13C NMR (100 MHz,
CDCl3) δ 165.3, 147.8, 141.2, 135.7, 132.3, 131.9, 131.2, 129.5, 127.6, 118.2, 114.4, 57.6, 47.6, 32.3, 30.6, 25.9, 25.7, 25.4,
24.0; HRMS (ESI): calcd for C25H33N2O+ [M+H]+ 377.2587, found 377.2578.
N-Isopropyl-2-(isopropyl(phenyl)amino)benzamide (12ba-H): the above procedure was applied to 119 mg of 2a, 38 mg of
8b, 4.3 L of H2O, and 76 mg of CsF to afford 42 mg of 12ba-H (71%) as a slightly yellow glass (containing a trace of
petroleum ether residue). 1H NMR (400 MHz, CDCl3):  8.21 (dd, J = 7.6, 1.9 Hz, 1 H), 7.68 (br, d, J = 6.5 Hz, 1 H), 7.47
(td, J = 7.5, 1.9 Hz, 1 H), 7.42 (td, J = 7.5, 1.4 Hz, 1 H), 7.20 (dd, J = 8.6, 7.4 Hz, 2 H), 7.09 (dd, J = 7.6, 1.2 Hz, 1 H), 6.78
(t, J = 7.3 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 2 H), 4.27 (sept, J = 6.5 Hz, 1 H), 4.09 (oct, J = 6.5 Hz, 1 H), 1.16 (d, J = 6.5 Hz, 6
H), 0.95 (d, J = 6.5 Hz, 6 H); 13C NMR (100 MHz, CDCl3): δ 165.2, 147.9, 141.3, 135.3, 131.93, 131.92, 131.2, 129.4, 127.6,
118.5, 114.9, 48.8, 41.2, 22.3, 20.3; HRMS (ESI): calcd for C19H25N2O+ [M+H]+ 297.1961, found 297.1964.
Methyl N-isopropyl-2-(isopropyl(phenyl)amino)benzimidate (12ba-Me): the above procedure was applied to 119 mg of 2a,
38 mg of 8b, 15 mg (2.4 equiv) of MeOH, and 76 mg of CsF to afford 52 mg of 12ba-Me (contaminated by a small quantity
of petroleum ether residue, NMR ratio product:PE (as dodecane) 100:6, corresponding to ~50 mg of pure 12ba-Me, 81%) as
yellow oil after chromatography on basic alumina. 1H NMR (400 MHz, acetone-d6):  7.49 (td, J = 7.8, 1.7 Hz, 1 H), 7.32 (td,
J = 7.4, 1.0 Hz, 1 H), 7.29–7.26 (m, 2 H), 7.09 (dd, J = 8.5, 7.4 Hz, 2 H), 6.69 (t, J = 7.3 Hz, 1 H), 6.64 (d, J = 8.0 Hz, 2 H),
4.22 (sept, J = 6.6 Hz, 1 H), 3.50 (s, 3 H), 3.25 (sept, J = 6.6 Hz, 1 H), 1.21 (d, J = 6.6 Hz, 6 H), 0.84–0.81 (br, 6 H) (this
compound may have two rotamers or E/Z isomers; some signals can be attributed to the minor rotamer/isomer: 7.21 (td, J =
8.8, 1.5 Hz), 6.94 (dd, J = 7.5, 1.3 Hz), 6.73 (d, J = 8.5 Hz), 3.70 (s), 3.71–3.68 (m), 3.31 (sept, J = 6.3 Hz), 1.17 (d, J = 6.3
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Hz), 1.02 (d, J = 6.2 Hz)); 13C NMR (100 MHz, acetone-d6):  158.8, 149.1, 145.1, 135.1, 131.6, 130.7, 130.6, 129.2, 126.2,
119.0, 118.3, 52.5, 51.7, 50.0, 25.1, 21.4 ; HRMS (ESI): calcd for C20H27N2O+ [M+H]+ 311.2118, found 311.2114.
Ethyl N-isopropyl-2-(isopropyl(phenyl)amino)benzimidate (12ba-Et): the above procedure was applied to 119 mg of 2a,
38 mg of 8b, 22 mg of EtOH (2.4 equiv), and 76 mg of CsF to afford 47 mg of 12ba-Et (contaminated by a small quantity of
petroleum ether residue, NMR ratio product:PE (as dodecane) 100:7, corresponding to ~45 mg of pure 12ba-Et, 69%) as a
yellow oil after chromatography on basic alumina. 1H NMR (400 MHz, acetone-d6): δ 7.49 (td, J = 7.6, 1.9 Hz, 1 H), 7.33 (td,
J = 7.3, 1.1 Hz, 1 H), 7.30–7.27 (m, 2 H), 7.08 (dd, J = 8.7, 7.3 Hz, 2 H), 6.67 (t, J = 7.3 Hz, 1 H), 6.62 (dd, J = 7.3, 0.9 Hz, 2
H), 4.26 (sept, J = 6.6 Hz, 1 H), 3.94 (q, J = 7.1 Hz, 2 H), 3.25 (sept, J = 6.1 Hz, 1 H), 1.22 (d, J = 6.6 Hz, 6 H), 1.05 (t, J =
7.1 Hz, 3 H), 0.87–0.83 (br, 6 H) (this compound may have two rotamers or E/Z isomers; some signals can be attributed to
the minor rotamer/isomer: 7.21 (td, J = 7.8, 1.6 Hz), 6.95 (dd, J = 7.4, 1.6 Hz), 6.73 (d, J = 8.2 Hz), 4.19 (q, J = 7.1 Hz), 3.68
(sept, J = 6.3 Hz), 3.33 (sept, J = 6.2 Hz), 1.17 (d, J = 6.3 Hz), 1.02 (d, J = 6.2 Hz)); 13C NMR (100 MHz, acetone-d6): 
158.3, 149.1, 144.7, 135.4, 131.8, 130.65, 130.56, 129.1, 126.3, 118.7, 118.5, 61.0, 51.3, 50.0, 25.2, 21.3, 14.4; HRMS (ESI):
calcd for C21H29N2O+ [M+H]+ 325.2274, found 325.2276.
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Isopropyl N-isopropyl-2-(isopropyl(phenyl)amino)benzimidate (12ba-Pr): the above procedure was applied to 119 mg of
2a, 38 mg of 8b, 29 mg of i-PrOH (2.4 equiv), and 76 mg of CsF to afford 45 mg of 12ba-Pr (contaminated by a small
quantity of petroleum ether residue, NMR ratio product:PE (as dodecane) 100:8, corresponding to ~43 mg of pure 12ba-Pr,
64%) as a yellow oil after chromatography on basic alumina. 1H NMR (400 MHz, acetone-d6): δ 7.50 (td, J = 7.7, 1.8 Hz, 1
H), 7.36 (td, J = 7.4, 1.1 Hz, 1 H), 7.30 (dd, J = 7.6, 1.7 Hz, 1 H), 7.27 (dd, J = 7.9, 0.8 Hz, 1 H), 7.07 (dd, J = 8.7, 7.3 Hz, 2
H), 6.64 (t, J = 7.3 Hz, 1 H), 6.58 (d, J = 8.0 Hz, 2 H), 4.98 (sept, J = 6.2 Hz, 1 H), 4.30 (sept, J = 6.6 Hz, 1 H), 3.25 (sept, J
= 6.1 Hz, 1 H), 1.22 (d, J = 6.6 Hz, 6 H), 1.07 (d, J = 6.2 Hz, 2 H), 0.87–0.83 (br, 6 H) (this compound may have two
rotamers or E/Z isomers; some signals can be attributed to the minor rotamer/isomer: 7.20 (td, J = 7.8, 1.6 Hz), 6.93 (dd, J =
7.4, 1.6 Hz), 6.74–6.70 (m), 5.22 (sept, J = 6.8 Hz), 3.68 (sept, J = 6.1 Hz), 3.32 (sept, J = 6.2 Hz), 1.26 (d, J = 6.2 Hz), 1.17
(d, J = 6.3 Hz), 1.01 (d, J = 6.2 Hz)); 13C NMR (100 MHz, acetone-d6): δ 157.4, 149.3, 144.1, 136.1, 132.4, 130.6 (2C),
129.1, 126.6, 118.2, 117.7, 67.0, 50.9, 50.0, 25.1, 21.9, 21.2; HRMS (ESI): calcd for C22H31N2O+ [M+H]+ 339.2431, found
339.2428.
2-Hydroxyethyl 2-(isopropyl(phenyl)amino)benzoate (12ba-G): the above procedure was applied to 119 mg of 2a, 38 mg
of 8b, 15 mg of ethylene glycol and 76 mg of CsF to afford 34 mg of 12ba-G (57% based on aryne, high-running spot, a
yellow oil, containing a trace of petroleum ether residue) and 12 mg of 11ba-G (18% based on carbodiimide, low-running
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spot)15 eluting with 10:7.5:1 petroleum ether/CH2Cl2/EtOAc. 12ba-G: 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J = 7.7, 1.6
Hz, 1 H), 7.60 (td, J = 7.7, 1.6 Hz, 1 H), 7.44 (td, J = 7.6, 1.0 Hz, 1 H), 7.22–7.15 (m, 3 H), 6.70 (t, J = 7.2 Hz, 1 H), 6.52 (d,
J = 8.1 Hz, 2 H), 4.31 (sept, J = 6.5 Hz, 1 H), 4.16–4.14 (m, 2 H), 3.46–3.44 (m, 2 H), 1.13 (d, J = 6.5 Hz, 6 H), OH not
observed; 13C NMR (100 MHz, CDCl3): δ 167.8, 148.4, 141.8, 133.9, 133.1, 133.0, 131.4, 129.0, 127.2, 116.6, 113.2, 67.0,
60.9, 48.5, 21.0; HRMS (ESI): calcd for C18H22NO3+ [M+H]+ 300.1594, found 300.1592.
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1-((2-(Isopropyl(phenyl)amino)phenyl)(isopropylimino)methyl)pyrrolidine-2,5-dione
(12ba-Su),
and
1-((2-(isopropylamino)phenyl)(isopropylimino)methyl)pyrrolidine-2,5-dione (11ba-Su): the above procedure was applied to
119 mg of 2a, 38 mg of 8b, 24 mg of succinimide and 76 mg of CsF to afford 28 mg of 12ba-Su (37% based on aryne,
high-running spot, a light yellow solid; mp 170 °C) and 11 mg of 11ba-Su (12% based on carbodiimide, low-running spot, a
yellow solid; mp 136–137 °C). 12ba-Su: 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J = 7.2, 2.1 Hz, 1 H), 7.52–7.45 (m, 2 H),
7.15–7.06 (m, 3 H), 6.70 (t, J = 7.2 Hz, 1 H), 6.40 (d, J = 6.5 Hz, 2 H), 4.26 (sept, J = 6.5 Hz, 1 H), 3.47 (sept, J = 6.1 Hz, 1
H), 2.32–2.24 (m, 2 H), 1.81–1.38 (m, 2 H), 1.26–1.21 (br, 6 H), 1.11–1.04 (br, 6 H) (this compound may have two rotamers
or E/Z isomers; some signals can be attributed to the minor rotamer/isomer: 7.62–7.54 (m), 7.21 (d, J = 7.8 Hz), 6.33 (d, J =
8.1 Hz), 4.34 (sept, J = 6.5 Hz), 3.86 (sept, J = 6.1 Hz)); 13C NMR (100 MHz, CDCl3): δ 174.7 (br), 148.0, 145.7, 140.5,
138.7, 133.2, 132.0, 121.5, 129.1, 128.2, 116.8, 113.7, 52.7, 48.4, 26.5, 23.0 (br), 19.6 (br); HRMS (ESI): calcd for
C23H28N3O2+ [M+H]+ 378.2176, found 378.2177. 11ba-Su: 1H NMR (400 MHz, CDCl3): δ 9.47 (br, 1 H), 7.16 (t, J = 7.5 Hz,
1 H), 6.86 (d, J = 7.9 Hz, 1 H), 6.68 (br, 1 H), 6.44 (br, 1 H), 3.65 (sept, J = 6.3 Hz, 1 H), 3.39 (sept, J = 6.1 Hz, 1 H),
2.94–2.82 (m, 4 H), 1.22 (d, J = 6.3 Hz, 6 H), 1.17 (d, J = 6.2 Hz, 6 H); 13C NMR (150 MHz, CDCl3): δ 174.9, 149.2 (br),
+
145.0, 132.1, 129.0, 113.7 (br), 112.0 (br), 111.6 (br), 52.5, 43.6 (br), 28.6, 24.4, 22.8; HRMS (ESI): calcd for C17H24N3O2
[M+H]+ 302.1863, found 302.1857.
N-(tert-Butyl)-2-(tert-butyl(phenyl)amino)benzamide (12ca-H): the above procedure was applied to 119 mg of 2a, 46 mg
of 8c, 4.3 L of H2O, and 76 mg of CsF to afford 23 mg of 12ca-H (35%) as a yellow oil (containing a trace of petroleum
ether residue). 1H NMR (400 MHz, CDCl3): δ 8.23 (brs, 1 H), 8.18 (dd, J = 7.4, 2.1 Hz, 1 H), 7.44–7.31 (m, 2 H), 7.16 (dd, J
= 8.7, 7.4 Hz, 2 H), 7.07 (dd, J = 7.5, 1.4 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 2 H), 6.80 (t, J = 7.3 Hz, 1 H), 1.45 (s, 9 H), 1.30 (s, 9
H); 13C NMR (100 MHz, CDCl3): δ 165.4, 147.7, 144.8, 136.0, 131.9, 131.4, 130.5, 128.6, 127.0, 119.6, 119.1, 57.2, 51.0,
29.1, 28.6; HRMS (ESI): calcd for C21H28N2NaO+ [M+Na]+ 347.2094, found 347.2093.
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N-(tert-Butyl)-2-(ethyl(phenyl)amino)benzamide (12da-H): the above procedure was applied to 119 mg of 2a, 38 mg of 8d,
4.3 L of H2O, and 76 mg of CsF to afford 24 mg of 12da-H (41%) as a slightly yellow glass (containing a trace of
petroleum ether residue). 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 7.8, 1.6 Hz, 1 H), 7.65 (brs, 1 H), 7.45 (td, J = 7.8, 1.5
Hz, 1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.20 (dd, J = 8.6, 7.4 Hz, 2 H), 7.12 (dd, J = 7.8, 0.8 Hz, 1 H), 6.80 (t, J = 7.3 Hz, 1 H),
6.67 (d, J = 8.0 Hz, 2 H), 3.66 (q, J = 7.1 Hz, 2 H), 1.23–1.19 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 165.2, 148.1, 144.1,
134.4, 132.0, 131.2, 129.8, 129.4, 127.0, 118.8, 114.5, 50.8, 46.7, 28.5, 12.3; HRMS (ESI): calcd for C19H25N2O+ [M+H]+
297.1961, found 297.1961.
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N-Isopropyl-2-(isopropyl(3-methoxyphenyl)amino)-6-methoxybenzamide (12bb-H): the above procedure was applied to
131 mg of aryne precursor 2b, 38 mg of 8b, 4.3 L of H2O, and 76 mg of CsF to afford 33 mg of 12bb-H (46%) as a white
solid; mp 90–91 ºC. 1H NMR (400 MHz, CDCl3): δ 7.37 (t, J = 8.1 Hz, 1 H), 7.04 (t, J = 8.1 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1
H), 6.75 (d, J = 7.8 Hz, 1 H), 6.23 (d, J = 7.2 Hz, 1 H), 6.05–6.02 (m, 2 H), 5.43 (d, J = 7.5 Hz, 1 H), 4.21 (sept, J = 6.4 Hz, 1
H), 3.99 (oct, J = 6.8 Hz, 1 H), 3.86 (s, 3 H), 3.72 (s, 3 H), 1.19 (d, J = 6.5 Hz, 6 H), 0.80 (d, J = 6.5 Hz, 6 H); 13C NMR (100
MHz, CDCl3): δ 165.3, 160.9, 158.0, 150.3 (br), 140.7, 130.6, 130.0, 129.0, 123.9, 110.3, 106.5 (br), 100.8 (br), 100.0 (br),
55.9, 55.1, 48.8 (br), 41.1, 22.0, 20.9; HRMS (ESI): calcd for C21H29N2O3+ [M+H]+ 357.2173, found 357.2168.
N-Isopropyl-2-(isopropyl(3/4-methoxyphenyl)amino)-4/5-methoxybenzamide (12bc-H,
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regioisomers): the above
procedure was applied to 131 mg of aryne precursor 2c, 38 mg of 8b, 4.3 L of H2O, and 76 mg of CsF to afford 56 mg of
12bc-H. This mixture can be separated into two fractions. The high-running fraction (33 mg) contains two regioisomers
(NMR ratio 1: 0.75, 46.5% combined yield, with a trace of petroleum ether residue). 1H NMR (400 MHz, CDCl3):  8.81 (d,
J = 5.9 Hz, 1 H, major), 7.81 (br, 1 H, major), 7.69 (dd, J = 2.3, 0.9 Hz, 1 H, minor), 7.56 (d, J = 6.5 Hz, 1 H, minor), 7.09 (t,
J = 8.2 Hz, 1 H, minor), 6.99–6.98 (m, 2 H, minor), 6.96–6.95 (m, 2 H, major), 6.77 (d, J = 9.0 Hz, 2 H, major), 6.68 (d, J =
8.9 Hz, 2 H, major), 6.32 (dd, J = 8.1, 1.9 Hz, 1 H, minor), 6.19 (dd, J = 8.3, 2.1 Hz, 1 H, minor), 6.16 (t, J = 2.3 Hz, 1 H,
minor), 4.24–4.03 (m, 2 H, major + 2 H, minor), 3.86 (s, 3 H, minor), 3.85 (s, 3 H, major), 3.73 (s, 3 H, major), 3.71 (s, 3 H,
minor), 1.13 (d, J = 6.3 Hz, 6 H, major), 1.12 (d, J = 6.4 Hz, 6 H, minor), 1.05 (d, J = 6.5 Hz, 6 H, major), 0.95 (d, J = 6.5 Hz,
6 H, minor); 13C NMR (150 MHz, CDCl3):d 165.1, 164.7, 160.8, 158.6, 158.0, 153.1, 149.6, 142.1, 136.4, 136.3, 134.6,
133.1, 133.0, 132.1, 130.2, 119.0, 118.7, 117.8, 114.6, 114.4, 114.0, 107.6, 102.7, 101.2, 55.53, 55.50 (2C), 55.1, 49.6, 48.8,
+
41.23, 41.19, 22.5, 22.3, 20.5, 20.3; HRMS (ESI): calcd for C21H29N2O3 [M+H]+ 357.2173, found 357.2174. The
low-running fraction (23 mg, contaminated by a small quantity of petroleum ether residue, NMR ratio product:PE (as
dodecane) 100:19, corresponding to ~21 mg of pure product) contains the other two regioisomers (NMR ratio 1:0.9, 29.5%
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combined yield), 1H NMR (400 MHz, CDCl3):  8.87 (br, 1 H, major), 8.28–8.26 (br, 1 H, major), 8.20 (d, J = 8.8 Hz, 1 H,
minor), 7.67–7.70 (br, 1 H, minor), 7.11 (t, J = 8.2 Hz, 1 H, minor), 6.95 (dd, J = 8.8, 2.5 Hz, 1 H, minor), 6.88 (d, J = 8.8 Hz,
1 H, major), 6.76–6.81 (br, 4 H, major), 6.57 (d, J = 2.5 Hz, 1 H, minor), 6.55 (br, 1 H, major), 6.36 (dd, J = 8.0, 2.0 Hz, 1 H,
minor), 6.25–6.21 (m, 2 H, minor), 4.25–4.05 (m, 2 H, major + 2 H, minor), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 3.72 (s,
3 H), 1.18–1.16 (m, 6 H, major isomer + 6 H, minor isomer), 1.08 (d, J = 6.1 Hz, 6 H, a signal for its rotamer comes at 1.04),
0.97 (d, J = 6.5 Hz, 6 H, a signal for its rotamer comes at 0.99); 13C NMR (150 MHz, CDCl3):  164.8, 164.8–164.7 (br),
162.2 (2C), 160.7, 153.5 (br), 149.0, 146.3, 142.6, 141.7–141.4 (br), 132.8, 132.7 (br), 130.1, 127.4, 119.1 (br), 117.0, 116.0
(br), 114.6 (2C), 112.9, 112.0–111.8 (br), 108.2, 103.1, 101.9, 55.5, 55.4 (2C), 55.1, 50.1 (br), 49.0, 41.0 (2C), 22.7, 22.4,
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13C NMR spectrum for the low-running fraction (see the SI). However, LC analysis (see the SI) shows that both fractions are
quite clean. This, together with the broadening of the signals, suggests that these “extra” signals are most likely rotamers or
E/Z isomers.
2-((3,4-Dimethoxyphenyl)(isopropyl)amino)-N-isopropyl-4,5-dimethoxybenzamide (12bd-H): the above procedure was
applied to 143 mg of aryne precursor 2d, 38 mg of 8b, 4.3 mg L of H2O, and 76 mg of CsF to afford 37 mg of 12bd-H as a
yellow glass (contaminated by a small quantity of petroleum ether residue, NMR ratio product:PE (as dodecane) 100:9,
corresponding to ~36 mg of pure 12bd-H, 43%). 1H NMR (400 MHz, CDCl3):  8.70 (d, J = 7.5 Hz, 1 H), 7.82 (s, 1 H), 6.75
(d, J = 8.8 Hz, 1 H), 6.47 (s, 1 H), 6.33 (dd, J = 8.8, 2.7 Hz, 1 H), 6.27 (d, J = 2.6 Hz, 1 H), 4.19–4.08 (m, 2 H), 3.94 (s, 3 H),
3.80 (s, 2 H), 3.77 (s, 3 H), 3.69 (s, 3 H), 1.15 (d, J = 6.6 Hz, 6 H), 1.04 (d, J = 6.6 Hz, 6 H); 13C NMR (100 MHz, CDCl3): δ
164.5, 151.4, 149.8, 147.6, 142.9, 142.3, 136.6, 126.4, 112.9, 112.5, 112.4, 107.8, 102.3, 56.3, 55.97, 55.92, 55.8, 49.6, 41.1,
22.6, 20.5; HRMS (ESI): calcd for C23H33N2O5+ [M+H]+ 417.2384, found 417.2375.
Methyl (4-chlorophenyl)(phenyl)carbamate (14): the above procedure was applied to 119 mg of 2a, 46 mg of 13, 8 mg of
MeOH, and 80 mg of CsF to afford 25 mg of 14 (contaminated by a small quantity of petroleum ether residue, NMR ratio
product:PE (as dodecane) 100:8, corresponding to 24 mg of pure 14, 38% based on MeOH) as a yellow oil. 1H NMR (400
MHz, CDCl3): δ 7.38–7.34 (m, 2 H), 7.31–7.17 (m, 7 H), 3.76 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 155.0, 142.1, 141.2,
131.6, 129.1, 129.0, 127.9, 127.0, 126.5, 53.2; HRMS (ESI): calcd for C14H1335ClNO2+ [M+H]+ 262.0629, found 262.0629.
Acknowledgment
This project was financially supported by the National Natural Science Foundation of China (No. 21002021 to F.S.),
Program for Science & Technology Innovation Talents in Universities of Henan Province (No. 13HASTIT010 to F.S.), the
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Program for Young Core Faculty (Henan Provincial Department of Education, to Chunrui Wu), and the “973 Program” (No.
2012CB619402 to H.T. and Chao Wu). We also thank the Materials Physics Center of FIST, Xi’an Jiaotong University for
providing computational resources, and Dr. Jiang Zhou (Peking University), Miss Jie Xiao (Shanghai Institute of Organic
Chemistry), and Mr. Bin Rao (Xi’an Jiaotong University) for their help in the spectroscopic analysis.
Supporting Information
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Computational details, full H and 13C NMR spectra of products and starting materials that are new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
References and Notes
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1
15. Data for by-product 11ba-G (2-hydroxyethyl 2-(isopropylamino)benzoate): off-white solid; mp 64–65 °C. H NMR (400
MHz, CDCl3): δ 7.94 (dd, J = 8.0, 1.3 Hz, 1 H), 7.37 (ddd, J = 8.4, 7.1, 1.3 Hz, 1 H), 6.78 (d, J = 8.5 Hz, 1 H), 6.61 (t, J = 7.5
Hz, 1 H), 4.42–4.39 (m, 2 H), 3.95–3.93 (m, 2 H), 3.73 (sept, J = 6.3 Hz, 1 H), 1.28 (d, J = 6.3 Hz, 6 H), OH shows a very
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