The Generation of Difluoroketenimine and Its Application in the Synthesis of α,α-Difluoro-β-amino Amides

Article abstract of DOI:10.1002/anie.201901591

Fluorine-containing β-amino acids and their derivatives have attracted significant attention due to their importance in life sciences. Herein the previously unknown difluoroketenimine, the analogue of the elusive difluoroketene, has been generated by the

Full text of DOI:10.1002/anie.201901591

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Accepted Article
Title: Generation of Difluoroketenimine and Its Application in the
Synthesis of α,α-Difluoro-β-amino Amides
Authors: Rui Zhang, Zhikun Zhang, Qi Zhou, Lefei Yu, and Jianbo
Wang
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Generation of Difluoroketenimine and Its Application in the
Synthesis of -Difluoro--amino Amides
Rui Zhang,† Zhikun Zhang,† Qi Zhou, Lefei Yu, and Jianbo Wang*
Abstract: Fluorine-containing β-amino acids and their derivatives
have attracted significant attentions due to their importance in life
sciences. Herein the previously unknown difluoroketenimine, as the
analogue of the elusive difluoroketene, has been generated by the
reaction of difluorocarbene and isocyanide, which further undergoes
[2+2] cycloaddition with imine. The three-component reaction affords
α,α-difluoro-β-amino amides in good yields. Mechanistic studies
reveal unique property of the difluoroketenimine in the [2+2]
cycloaddition with imine.
β-Amino acids, and their derivatives have profound importance
in various fields, for example as the building blocks of β-
peptides.[1] Staudinger reaction, namely [2+2] cycloaddition of
ketene with imine, represents one of the most important
approaches toward β-lactams,[2,3] which can be further converted
into β-amino acids or their derivatives through ring-opening
hydrolysis (Scheme 1a). On the other hand, the introduction of
fluorine atom into organic molecules often leads to significant
modification of their physical, chemical and biological
properties.[4] As a consequence, α,α-difluoro-β-lactams and their
derivatives have attracted much attentions for their potential
applications in medicinal chemistry and important role in the
preparation of α,α-difluoro-β-amino carbonyl compounds.[5,6]
Scheme 1. Staudinger synthesis and proposed [2+2] cycloaddition with
difluoroketenimine.
However, the previously developed synthetic methods are in
general hampered by their tedious multi-step routes and the
availability of fluorine sources. New and convenient method for
some initial efforts based on this hypothesis proved to be futile.
The expected α,α-difluoro-β-lactam was not observed.
the introduction of α,α-difluoro-β-amino moiety is still highly
demanded.
As isocyanides have been explored as the surrogate of
carbon monoxide because of the similarity of their reactivity,[13,14]
we further conceived that as the analogue of difluorocarbene,
the difluoroketenimine might be obtained through the reaction of
difluorocarbene and isocyanide. Ketenimines are in general less
reactive as compared with their ketene counterparts and
ketenimine-imine [2+2] reactions are rare.[15,16] To the best of our
knowledge, difluoroketenimines are not documented in the
literature. It can be expected that the introduction of fluorine
substituents on the C-terminus activate the ketenimines, thus
possibly leading to facile [2+2] cycloaddition to give α,α-difluoro-
β-lactams or α,α-difluoro-β-amino acid derivatives after
hydrolysis (Scheme 1c). Herein, we report the study along this
line, in which the [2+2] reaction of imines and
difluoroketenimines generated in situ via the reaction of
difluorocarbene and isocyanides. The three-component reaction
provides a straightforward access toward α,α-difluoro-β-amino
amides and α,α-difluoroazetidinimines.
In the initial test of the hypothesis, (bromodifluoromethyl)tri-
methylsilane 3 was chosen as the difluorocarbene precursor,
which reacted with tert-butylisocyanide 2a and benzylidene-
methane-sulfonamide 1a in the presence of tetra-n-
butylammonium bromide (TBAB) as the initiator for generating
difluorocarbene.[17] The reaction proceeded smoothly in DCE at
50 oC, however, upon work-up with acid, the initially expected β-
lactam 4a could not be detected and only 5a was obtained in
51% 19F NMR yield (Table 1, entry 1). The structure of 5a was
As Staudinger synthesis has been widely applied in the
preparation of β-lactams, therefore, we envisioned whether this
powerful method could be used to access α,α-difluoro-β-lactams
through the reaction of imines and difluoroketene.[7] However, a
survey of the literature indicates that difluoroketene is quite
unstable and it facilely undergoes decomposition to generate
CO and difluorocarbene.[7a] In 2004, Bergman et al. reported an
iridium stabilized difluoroketene, which provided the only
structural information for difluoroketene in any form.[8] In view of
the fact that carbonylation of Fischer-type carbene with CO is a
straightforward method for generating ketene,[9,10] we have
hypothesized that difluoroketene may be generated directly from
CO and difluorocarbene, which has recently attracted attentions
as a type of electrophilic carbene[11,12] (Scheme 1b). However,
[*]
R. Zhang, Z. Zhang, Q. Zhou, L. Yu, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry
Peking University, Beijing 100871, China
E-mail: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Lu, Shanghai 200032, China
[†]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901591
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unambiguously determined by X-ray diffraction. Various work-up
conditions were examined but only the ring-opening product 5a
was obtained exclusively rather than the β-lactam 4a, which was
attributed to the strong electron-withdrawing Ms group that
destabilized the four-membered ring under acidic conditions
(vide infra). Considering the fact that α,α-difluoro-β-amino
amides are important building blocks in pharmaceuticals,[18] we
proceeded to optimize the reaction conditions for yielding 5a. By
adding 2a dropwise to avoid its decomposition, the yield of 5a
could be improved to 69% (Table 1, entry 2). The yield slightly
increased to 71% with less TBAB (Table 1, entry 3). Further
screening of the temperature indicated that optimal results could
be obtained at 60 oC (Table 1, entries 4-6). When the loading of
either component was reduced, the yield decreased dramatically
(Table 1, entries 7, 8). Finally, the reaction was run in 0.2 mmol
scale with higher concentration and 5a was isolated in 90% yield
(Table 1, entry 9).
Table 1. Optimization of the reaction conditions[a]
entry
1a:2a:3
TBAB (mol%)
T (oC)
Yield[b]
1
1:2:2
1:2:2
50
50
30
30
30
30
30
30
30
50
50
50
40
60
70
60
60
60
51%
69%
71%
56%
85%
83%
67%
34%
90%[e]
2[c]
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9[c,d]
1:2:2
1:2:2
1:2:2
1:2:2
1:2:1.5
1:1.5:2
1:2:2
Scheme 2. Substrate scope of N-sulfonyl imines. Reaction conditions:
1:2:3:TBAB = 0.2:0.4:0.4:0.06 (mmol), in 1.5 mL DCE at 60 oC for 4 h. For 1a-r,
1v-x, the solution of 2 in 0.5 mL DCE was added dropwise over 0.5 h. For 1s-
u, the solution of 1 and 2 was added dropwise simultaneously over 0.5 h.
Work-up conditions: in 1.5 mL THF with aq. HCl (1 mL, 3M) for 10 min. [a] All
the yields refer to the isolated products after column chromatography on silica
gel. [b] Thermal ellipsoids shown at 30% probability for the X-ray structure of
5a.
[a] The reactions were run on 0.2 mmol scale in 2 mL DCE. [b]The yields
before work-up with acid were determined by 19F NMR with PhCF3 as the
internal standard. The yield of the work-up step is quantitative. [c] The solution
of 2a in 0.5 mL DCE was added dropwise in 0.5 h. [d] 1.5 mL DCE was used.
[e] Isolated yield of 5a with chromatography column on silica gel. TBAB: tetra-
n-butylammonium bromide; DCE: 1,2-dichloroethane.
of 1l proceeded smoothly to give 1.41 g of 5l in 93% yield. Other
sulfonyl protecting groups (5p-r) also give excellent yields. For
aliphatic imines, N-Ts imines were used instead because they
could be easily prepared. Since aliphatic imines are unstable
and easy to undergo hydrolysis under the conditions, in these
cases imines and isocyanides were added dropwise
simultaneously. Improved results could be obtained under such
conditions. Primary aliphatic imines afforded the corresponding
products in good yields (5s, 5t). Nevertheless, bulkier imines
only afforded the product in moderate yield, due to the steric
hindrance of the cyclohexyl group (5u). Furthermore, it was
found that the reaction was quite sensitive to the structure of
isocyanides. Cyclohexyl isocyanide resulted in 55% yield (5w),
while the primary isocyanide gave modest yield (5x). This is
probably because less sterically hindered isocyanides are less
stable and decompose rapidly under the reaction conditions.
With the optimized conditions, the substrate scope was further
evaluated with imines and isocyanides. As illustrated in Scheme
2, imines with various substituents on the aromatic ring were
well tolerated. Substrates bearing electron-withdrawing groups
(5d-h, 5l) or weak electron-donating groups (5b, 5c) reacted
smoothly to give the corresponding products in good to excellent
yields, while the methoxy group resulted in slightly diminished
yield (5i). The substrates bearing ortho-substituent also gave the
corresponding product in good yields (5j, 5k, 5m), indicating that
steric effects have little influence on the reaction. Other aromatic
groups including naphthalene (5n) and thiophene (5o) also
demonstrated excellent compatibility in this transformation. The
reaction could be readily scaled up to gram-scale. The reaction
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Since the strong electron-withdrawing Ms group of the imine
substrates hampered the formation of β-lactams in the
hydrolysis of the [2+2] cycloaddition products, different
substituents on the nitrogen were examined. N-Boc, N-OMe, N-
acetyl and N-sulfinyl imines resulted in a sluggish mixture of
unidentified products. Gratifyingly, N-Ar imines gave the
expected [2+2] product. Under the slightly modified conditions,
the reaction with N,1-diphenylmethanimine 6a gave the
azetidinimine product 7a in 55% isolated yield. 7a is more stable
than its Ms analogue and can be isolated via preparative thin-
layer chromatography. As is shown in Scheme 3, imines with
electron-donating groups (6c, 6e, 6f, 6h) and electron-
withdrawing groups (6b, 6d, 6g) on both aryl rings were
tolerated and gave the corresponding azetidinimine products in
moderate yield. Acidic hydrolysis of the reaction mixture of 7a-h
without purification yielded the corresponding β-lactam products
together with ring-opening products α,α-difluoro-β-amino amides
(see Supporting Information for details).
and -130 ppm in 19F NMR spectrum. Analysis of the residue of
the reaction with high resolution mass spectrum (HRMS)
successfully detected molecular weights of dimer and trimer of 8
but they were not stable enough to be isolated for further
characterization (Scheme 4a). To further elucidate the
generation of difluoro ketenimine 8, a trapping experiment was
carried out (Scheme 4b). After heating the mixture of 2a, 3 and
TBAB for 15 min, p-toluenesulfonamide (TsNH2) was added and
the signal of 8 was quickly quenched. The product 9 derived
from the reaction of difluoroketenimine 8 and TsNH2, was
isolated in 58% yield (Scheme 4b, see Supporting Information,
Figure S6). These results provided evidence to support the
hypothesis that difluorocarbene react with isocyanide to afford
difluoroketenimine intermediate 8.
Next, to verify the hypothesis that final product is generated
through difluoroketenimine intermediate; imine 1l was added to
the mixture of 2a, 3 and TBAB after heating at 60 oC for 15 min.
The progress of the reaction was monitored by 19F NMR. It was
observed that the singlet signal proposed for
8 soon
disappeared and the signals proposed to be of four-membered
ring intermediate 10l appeared (Scheme 4c, see Supporting
Information, Figure S7). The existence of the proposed
intermediate 10l could be supported by both 19F NMR and
HRMS (see Supporting Information, Fig. S7 and Fig. S8).
However, unlike azetidinimines 7a-h, 10l is not stable due to the
strong electron-withdrawing Ms substituent.
Scheme 3. Substrate scope of N-aryl imines. Reaction conditions:
1:2:3:TBAB = 0.2:0.4:0.4:0.06 (mmol), in 1.5 mL DCE at 60 oC for 4 h. For 1a-r,
1v-x, the solution of 2 in 0.5 mL DCE was added dropwise over 0.5 h. For 1s-
u, the solution of 1 and 2 was added dropwise simultaneously over 0.5 h.
Work-up conditions: in 1.5 mL THF with aq. HCl (1 mL, 3M) for 10 min. All the
yields refer to the isolated products.
This three-component transformation, particularly the
formation of difluoro-ketenimine and its reactivity toward imine
nucleophiles, raises intriguing mechanistic questions. To gain
insights into the details of the reaction, a series of control
experiments were carried out (Scheme 4). According to our
hypothesis shown in Scheme 1c, difluoroketenimine is first
generated, followed by [2+2] cycloaddition to give four-
membered ring intermediate. To prove the existence of
difluoroketenimine, a mixture of 2a, 3 and 30% TBAB was
Scheme 4. Experiments for mechanistic understanding.
o
heated at 60 C and the reaction was monitored by 19F NMR
Based on the experiment observation and the previous
understanding of Staudinger reaction,[3] three possible pathways
could be proposed for the [2+2] cycloaddition (Scheme 5).
using trifluorotoluene as the internal standard. The generation of
difluorocarbene via α-elimination of 3 has been previously
documented.[17,19] This was also supported by the formation of
CF2BrH observed in 19F NMR (see Supporting Information,
Figure S1 and Figure S2) in this experiment. After 3 min, a
singlet of -145.7 ppm appeared, which could be assigned to the
signal of difluoroketenimine 8 (Scheme 4a). The yield of the
intermediate reached its maximum, about 3% after 15 min, and
remained constant, until the carbene precursor 3 was totally
consumed after 4 h (see Supporting Information, Figure S1-4).
During the process some signals were observed between -100
Pathway
A features a two-step mechanism, initiated by
nucleophilic attack on difluoroketenimine by the nitrogen
terminus of imine to generate a zwitterionic species, followed by
a fast intramolecular cyclization. In pathway B, the initial step is
nucleophilic attack on the carbon of imine by the terminal carbon
of difluoroketenimine, giving a zwitterionic species which is
followed by cyclization. The difference of path A and B is that in
the former a C-N bond is formed in advance of the formation of
C-C bond, however, in the latter, a C-C bond is formed at first. In
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contrast, pathway C refers to a concerted [2+2] process. This
mechanism is conventionally proposed for ketene-olefin [2+2]
reactions.[20] In the literatures, both computational and
experimental studies suggest that ketene-imine [2+2] reaction
favors path A.[3,21] The [2+2] reaction between imines and
keteniminium cations was reported to proceed in a similar
way.[22] Some previous report of ketenimine-imine [2+2] reaction
support path A as well, albeit without convincible experimental
In summary, we have reported an approach toward
difluoroketimine through the reaction of difluorocarbene with
isocyanide. An efficient synthesis of α,α-difluoro-β-amino amides
and α,α-difluoroazetidinimines have been developed based on
the [2+2] reaction of imines and the in situ generated
difluoroketenimine. Mechanistic studies have substantiated the
existence of difluoroketenimine intermediate and revealed an
unusual stepwise mechanism of [2+2] reaction.
t
evidence.[16] However, we envision that Ms of the imine and Bu
substituent of the nitrile moiety might stabilize the negative and
positive charges in the zwitterion generated in pathway B,
respectively, making pathway B plausible.
Acknowledgements
We are grateful to National Basic Research Program of China
(973 Program, No. 2015CB856600) and Natural Science
Foundation of China (21871010) for the financial support.
Conflict of interest
The authors declare no conflict of interest.
Keywords: carbene · fluorine · difluoroketenimine · [2+2]
reaction · -amino amide
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correlation.
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Rui Zhang, Zhikun Zhang, Qi Zhou,
Lefei Yu, and Jianbo Wang*
Page No. – Page No.
Generation of Difluoroketenimine and
Its Application in the Synthesis of
-Difluoro--amino Amide
Difluoroketenimine, as the analogue of the elusive difluoroketene, has been
generated for the first time by the reaction of difluorocarbene and isocyanide, which
further undergoes [2+2] cycloaddition with imine. The three-component reaction
affords -difluoro--amino amides in good yields. Mechanistic studies reveal
unique property of the difluoroketenimine in the [2+2] cycloaddition with imine.
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