Phosphine-Catalyzed Difunctionalization of β-Fluoroalkyl α,β-Enones: A Direct Approach to β-Amino α-Diazo Carbonyl Compounds

Article abstract of DOI:10.1002/anie.201810253

An efficient and practical phosphine-catalyzed vicinal difunctionalization of β-fluoroalkyl α,β-enones with TMSN₃ has been developed. Using dppb as the catalyst, the reaction worked efficiently to yield various β-amino α-diazocarbonyl compounds in high yields (up to 94 %). This work marks the first efficient construction of α-diazocarbonyl compounds by phosphine catalysis. Meanwhile, the asymmetric variant induced by the nucleophilic bifunctional phosphine P4 led to various chiral fluoroalkylated β-amino α-diazocarbonyl compounds in high yields and enantioselectivity. NMR and ESI-MS studies support the existence of the key reaction intermediates. In contrast, β-azide carbonyl compounds would be furnished in good yields from β-fluoroalkylated β,β-disubstituted enones.

Full text of DOI:10.1002/anie.201810253

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Unexpected Phosphine-Catalyzed Difunctionalization of β-
Fluoroalkyl α,β-Enones: A Direct Approach to β-Amino α-Diazo
Carbonyl Compounds
Authors: Junliang Zhang, Huamin Wang, Li Zhang, Youshao Tu, Ruiqi
Xiang, and Yinlong Guo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810253
Angew. Chem. 10.1002/ange.201810253
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10.1002/anie.201810253
Angewandte Chemie International Edition
COMMUNICATION
Phosphine-Catalyzed Difunctionalization of -Fluoroalkyl ,-
Enones: A Direct Approach to -Amino -Diazo Carbonyl
Compounds
Huamin Wang,[a] Li Zhang,[b] Youshao Tu,[a] Ruiqi Xiang[a] Yin-Long Guo,* [b] and Junliang Zhang*[b,c]
Dedicated to Professor Xiyan Lu for his 90th birthday
Abstract: An efficient and practical phosphine-catalyzed vicinal
difunctionalization of -fluoroalkyl ,-enones with TMSN3 has been
developed. Using DPPB as the catalyst, the reaction worked
efficiently to yield various -amino -diazocarbonyl compounds in
high yields (up to 94%). This work marks the first efficient
construction of -diazocarbonyl compounds by phosphine catalysis.
Meanwhile, the asymmetric variant induced by the nucleophilic
bifunctional phosphine P4 led to various chiral fluoroalkylated -
amino -diazocarbonyl compounds in high yields and
enantioselectivity. NMR and ESI-MS studies support the existence of
the key reaction intermediates. In contrast, -azide carbonyl
compounds would be furnished in good yields from -fluoroalkylated
,-disubstituted enones.
than the release of a molecule of N2. To the best of our
knowledge, the introduction of three nitrogen atoms of azide into
organic compounds via Staudinger phosphazide intermediate
without requiring stoichiometric amount of phoshine or extra
reductant has not been reported thus far, and if it works, which
will further improve the atom-economy and enrich the azide
chemistry.
During our continuous efforts in developing phosphine-
catalyzed[6,7] diverse transformations[8], we envisaged that the
phosphazide zwitterion intermediate might be competitively
trapped with a electrophile, i.e. enones by slowing down the
generation of the iminophosphorane, involving intramolecular
nucleophilic addition to generate the key triazole intermediate,
subsequent fragmentation of generated -amino -diazo
carbonyl compounds. If this hypothesis succeeds, we may open
a new window for transformations of azide into synthetic useful
compounds with the use of phosphine catalyst. Herein we
reported the first enantioselective phosphine-catalyzed
difunctionalization of alkene by -fluoroalkylated ,-enone with
TMSN3, furnishing a facile access to fluoroalkylated -amino -
diazo carbonyl compounds (Scheme 1d). Further study has
revealed that the fluorine effect plays a very important role in this
transformation.
zides, as a class of significant valuable building blocks,
have been utilized to construct many usful frameworks.[1] In
A
past decades, many methods has been developed for azide-
involved transformations with classical phosphine-mediated[2] or
-catalyzed reactions.[3] Among these methods, the Staudinger
reaction has received much attention in the field of chemistry
and chemical biology.[2a-d] This reaction proceeds through
nucleophilic addition of the phosphine at the terminal nitrogen
atom of the azide to form a phosphazide intermediate, the
iminophosphorane was then formed after releasing a molecular
of N2.[2b,d] It’s fameous name reactions were then developed by
traping the iminophosphorane intermediate of Staudinger
reaction. For example, Staudinger reduction reaction is the
iminophosphorane intermediate reacting with water to produce
the amide (Scheme 1a). Besides the water, the phosphazide
intermediate could be traped by carboxylic acid derivatives,
leading to amide product, which is called Staudinger ligation
(Scheme 1b).[2e,f,] In 2013, a significant contribution was made
by Raines,[4,5] demonstrating the efficient conversion of azides
into diazo compounds in phosphate buffer at neutral pH at room
temperature (Scheme 1c). In this elegant work, the reaction
proceeds through the decomposition of an acyl triazene rather
[a] H. Wang, R. Xiang
Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering,
East China Normal University
Shanghai, 200062 (P. R. China)
Scheme 1. Phosphine-involved azide conversion.
[b] L, Zhang, Prof. Dr. Y.-L. Guo* and J. Zhang*
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P. R.China)
[c] Prof. Dr. J. Zhang*
Department of Chemistry
In order to slow down the N2-releasing step from phosphazide
zwitterion intermediate to the iminophosphorane , we selected
TMSN3 with a bulky TMS group as the azide. The reaction of
TMSN3 with -perfluoroalkyl enone (Z)-1a or (E)-1a indeed
worked smootly in toluene under argon atmosphere in the
presence of 10 mol% of 1,4-bis(diphenylphosphino)butane
(DPPB), delivering -amino -diazo carbonyl compound 2a in
81% yield (Table 1, Entry 1 and 2). Aryl enones bearing
electron-donating, halogen or electron-withdrawing substituent
on phenyl ring were successfully converted to the corresponding
diazo products in moderate to excellent yields (55-92%, 2b-2n)
Fudan University
2005 Songhu Road, Shanghai, 200438 (P. R. China)
E-mail: ylguo@sioc.ac.cn
junliangzhang@fudan.edu.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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10.1002/anie.201810253
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COMMUNICATION
(Table 1, Entries 3-15). The structures of diazo compounds 2
were further confirmed by the X-ray single crystal analysis of
2e.[9] Moreover, substrates bearing methanesulfonyl and
methylthio group on the aryl ring were also smoothly converted
to the desired diazo product 2o (78%) and 2p (69%),
respectively (Table 1, Entry 16 and 17). The reactions of ortho-
and meta-substituted aryl enones delivered 2q-2t in good yields
(Table 1, Entries 18-21). Multiply substituted aryl enones also
worked well, affording 2u-2v in moderate to good yields (48-
70%) (Table 1, Entry 22 and 23). Moreover, naphthyl- and
heteroaryl-substituted diazo compounds 2w-2aa could be also
obtained in 50-94% yields (Table 1, Entries 24-28). To our
delight, aliphatic enones such as cyclohexyl (1ba) and
cyclohexenyl (1ca) also proceeded smoothly to furnish the
desired products, albeit with relatively lower efficiency (Table 1,
Entry 29 and 30). Furthermore, the trifluoromethyl group could
be replaced by other perfluoroalkyl group such as
perfluoropropyl, perfluoroethyl and even difluoromethyl group,
furnishing moderate to good yields of the desired diazo products
2da, 2ea, and 2fa (Table 1, Entries 31-33). It is noteworthy that
ethyl 4,4,4-trifluorocrotonate was also applicable to give 2ga in
reasonable yield (Table 1, Entry 34). When the TIPSN3 and
TESN3 instead of TMSN3, the reaction still proceeded smoothly
and gave the corresponding product 2g in 57% and 71% yields,
respectively (Table 1, Entries 35 and 36).
After establishing a general and reliable method for the
synthesis of unprecedented fluoroalkylated -amino -diazo
carbonyl compounds, we next focused on the development of an
enantioselective version mediated by a chiral phosphine. To our
delight, using chiral sulfinamide phosphines P1 as the catalyst,
enone 1g and TMSN3 were reacted in toluene at room
temperature, giving chiral -amino -diazo carbonyl compound
2g in 40% yield and promising enantioselectivity (e.r. 55.5:44.5)
(Table 2, entry 1). An array of other chiral phosphine amide
catalysts were also examined, We were pleased to discover that
using catalyst P48f, bearing a bulky 3,5-di-tert-butylphenyl
substituent, product (-)-2g was obtained in 61% yield with e.r. of
89.5:10.5 (Table 2, entries 2-7). The dipeptide backbone catalyst
gave inferior enantioselectivity and yield (Table 2, entry 8).
Survey of the solvents revealed that o-xylene was the choice in
terms of enantioselectivity (Table 2, entries 9-12). When
increasing the catalyst loading from 10 to 20 mol%, gave a
increase in yield (Table 2, entry 13). Lowering the reaction
temperature to 0 oC inhibited the reaction (Table 2, entry 14).
Table 2: Asymmetric difunctionalization of -perfluoroalkyl enone 1g
to TMSN3 catalyzed by phosphines.[a]
Table 1: Scope of the perfluoroalkylated ,-enones.[a]
Entry
1
2
3
4
5
6
7
8
1, R1
E-1a,Ph
Z-1a
Rf
2, Yield (%)[b]
2a, 81
2a, 79
2b, 80
2c, 79
2d, 92
2e, 78
2f, 73
2g, 73
2h, 75
2i, 70
2j, 69
2k, 60
2l, 55
2m, 63
2n, 82
2o, 78
2p, 69
2q, 76
2r, 78
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C3F7
CF2H
CF3
CF3
CF3
1b, 4-MeC6H4
1c, 4-isobutylphenyl
1d, 4-MeOC6H4
1e, 4-PhC6H4
1f, 4-FC6H4
1g, 4-ClC6H4
1h, 4-BrC6H4
1i, 4-IC6H4
1j, 4-F3COC6H4
1k, 4-F3CC6H4
1l, 4-NO2C6H4
1m, 4-CNC6H4
1n, 4-MeO2CC6H4
1o, 4-MeO2SC6H4
1p, 4-MeSC6H4
1q, 2-NO2C6H4
1r, 3-NO2C6H4
1s, 3-FC6H4
1t, 3-BrC6H4
1u, 3,4-Cl2C6H3
1v, 3,4-(CF3)2C6H3
1w, 1-naphthyl
1x, 2-naphthyl
1y, 2-benzothienyl
1z, 2-furyl
9
10
11
12
13
14
15
16[c]
17
18
19
20
21
22
23
24
25
26
27
28[d]
29
30
31
32
33
34
35e
36f
Entry
1
2
3
4
5
6
7
8
Cat
P1
P2
P3
P4
P5
P6
P7
P8
P4
P4
P4
P4
P4
P4
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
CHCl3
THF
o-xylene
o-xylene
o-xylene
Yield [%]b]
40
55
45
61
60
55
70
50
66
68
69
60
77
trace
E.r.[c]
55.5:44.5
74:26
83:17
89.5:10.5
82.5:17.5
76.5:23.5
88.5:11.5
76:24
83.5:16.5
86.5:13.5
81:19
2s, 70
2t, 75
9
10
11
12
13[d]
14[d,e]
2u, 70
2v, 48
2w, 73
2x, 94
2y, 50
2z, 72
2aa, 63
2ba, 50
2ca, 43
2da, 84
2ea, 87
2fa, 67
2ga, 33
2g, 57%
2g, 71%
91.5:8.5
91.5:8.5
--
1aa, 2-pyridyl
1ba, cyclohexyl
1ca, 1-cyclohexenyl
1da, Ph
1ea, Ph
1fa, Ph
1ga, EtO
1g
1g
[a] Reaction conditions: 1g (0.1 mmol), TMSN3 (0.2 mmol), and the catalyst
(0.01 mmol) in the solvent specified (1 mL) at room temperature for 10 h. [b]
19F NMR yield with PhCF3 as an internal standard. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] P4 was used 20 mol%. [e] At 0 oC.
THF = Tetrahydrofuran. CHCl3 = Chloroform.
With the optimal reaction conditions in hand, we were
subsequently to explore the generality of this reaction with a
variety of -perfluoroalkyl enones, and the results are shown in
Table 3. The substituents containing electron-withdrawing
groups, and electron-donating groups on aromatic ring moiety of
enones 1a−e were well tolerated and resulted in good yields
(69−91%) and with good enantioselectivities (Table 3, entries 1-
14). The absolute configuration of the resulting in (-)-2e was
[a] Reactions were performed with 1 (0.2 mmol), TMSN3 (0.4 mmol), and
DPPB (0.02 mmol) in toluene (1.0 mL) at room temperature . [b] Yield of
isolated product. [c] Carried out in 2 mL of toluene/DCM (V:V = 1:1). [d] Using
Ph2PCH3 (10 mol%) as catalyst. [e] TIPSN3 instead of TMSN3. [f] TESN3
instead
of
TMSN3.
TMSN3
=
azidotrimethylsilane.
TIPSN3
=
azidotriisopropylsilane. TESN3 = azidotriethylsilane. DCM = Dichloromethane.
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10.1002/anie.201810253
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COMMUNICATION
unambiguously determined to be (R) by an X-ray
2e by Ac2O in dichloromethane provided the product 5e in 71%
yield with e.r. of 92.5:7.5.
crystallographic
analysis.[9]
However,
strong
electron-
withdrawing group on the aryl seemed to lead to slightly
decresed e.r. (Table 3, entries 9-11). Moreover, benzen- and
heteroaryl-fused enones are also suitable substrates, affording
products (-)-2w-2z in good yields and stereoselectivity (Table 3,
entries 15-18). In addition to trifluoromethyl enones, other
fluoroalkyl enone, including pentafluoroethyl enone 1da,
heptafluoropropyl enone 1ea, and difluoromethyl enone 1fa,
were examined, which also worked smoothly with the protocol
(Table 3, entries 19-21). In addition, some other silicon azides
were synthesized, and evaluated for reaction with 1a under the
optimized reaction conditions. TBSN3 and TESN3 are also well
tolerated, affording (-)-2a with e.r. of 89:11 and e.r. of 90:10,
respectively (Table 3, Entries 22 and 23).
Table 4: Substrate scope of azidation of ,-unsaturated ketones[a,b]
.
Table 3: Scope of the catalytic enantioselective difunctionalization of
-perfluoroalkyl enone 1 to TMSN3.[a]
[a] Reactions were performed with 1 (0.2 mmol), TMSN3 (0.4 mmol), and
DPPB (0.02 mmol) in toluene (1.0 mL) at room temperature . [b] Yield of
isolated product.
Entry
1
2
3
4
5
6
7
8
1, R1/Rf
1a, Ph/CF3
(-)-2, Yield [%][b]
(-)-2a, 88
(-)-2b, 74
(-)-2c, 79
(-)-2d, 74
(-)-2e, 91
(-)-2f, 82
(-)-2g, 79
(-)-2h, 82
(-)-2j, 80
(-)-2k, 86
(-)-2m, 79
(-)-2n, 90
(-)-2p, 69
(-)-2u, 89
(-)-2w, 85
(-)-2x, 76
(-)-2y, 63
(-)-2z, 80
(-)-2da, 86
(-)-2ea, 88
(-)-2fa, 58
(-)-2a, 60
(-)-2a, 65
E.r [c]
92.5:7.5
92.5:7.5
92:8
92.5:7.5
92.5:7.5
91:9
91.5:8.5
91:9
87.5:12.5
1b, 4-MeC6H4/CF3
1c, 4-isobutylphenyl/CF3
1d, 4-MeOC6H4/CF3
1e, 4-PhC6H4/CF3
1f, 4-FC6H4/CF3
1g, 4-ClC6H4/CF3
1h, 4-Br C6H4 /CF3
1j, 4-F3COC6H4/CF3
1k, 4-F3CC6H4/CF3
1m, 4-CNC6H4/CF3
1n, 4-MeO2CC6H4/CF3
1p, 4-MeSC6H4/CF3
1u, 3,4-Cl2C6H3/CF3
1w, 1-naphthy/CF3
1x, 2-naphthy/CF3
1y, 2-benzothienyl/CF3
1z, 2-furyl/CF3
9
10
11
12
13
14
15
16
17
18
19
20
21
22[d]
23[e]
86:14
87.5:12.5
91:9
93:7
Scheme 2. Synthetic transformations of (-)-2e.
87:13
93.5:6.5
92.5:7.5
90.5:9.5
90:10
90:10
91:9
90:10
89:11
90:10
1da, Ph/C2F5
1ea, Ph/C3F7
1fa, Ph/CF2H
1a
1a
[a] Reactions were performed with 1 (0.1 mmol), TMSN3 (0.2 mmol) and P4
(0.02 mmol) in o-xylene (1.0 mL) at room temperture. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase. [d]
TBSN3 instead of TMSN3. [e] TESN3 instead of TMSN3. TBSN3 = azido(tert-
butyl)dimethylsilane.
Scheme 3. Proposed mechanism.
A plausible reaction mechanism is proposed in Scheme 3.
The reaction was initiated by the nucleophilic addition of the
phosphine at the terminal nitrogen atom of the azide providing
the phosphazide zwitterionic intermediate IA. Then the
nucleophilic attack of phosphazide zwitterion intermediate IA to
-fluoroalkylated ,-enone 1 results in enolate intermediate IB,
which intramolecular nucleophilic addition to generate
intermediate IC. Subsequent -elimination of the phosphine
catalyst and hydrolysis[10] leads to the cycloadduct ID, which
rapidly undergoes further fragmentation[11] to give the final -
amino -diazocarbonyl compounds.
To gain insight the reaction pathway, some control
experiments (Supporting Information, Figure S1) and a series of
experiments monitored by 19F NMR spectroscopy and 31P NMR
(Fig. S2-S4) were carried out. The substrate 1g alone showed a
19F resonance signal at -64.85 ppm and the product 2g alone
showed a 19F resonance signal at -77.17 ppm. When mixing
It is very interesting to find that the introduction of the second
-substituent to the -trifluoromethyl enones would deliver the
azide products 3a-3g in 77-92% yields via the direct conjugate
azidation reaction instead of diazo compounds (Table 4). The
structure of azide compound 3d was further sconfirmed by the
X-ray single crystal analysis.[9] The reactions of ,-diester
enone and 3-aroyl acrylates also delivered the azide compound
rather than the diazo compound with the use of Ph2PCH3 as
catalyst, indicating the structure of the enones affect the reaction
significantly, but the detailed reason is not clear.
Synthetic transformations of the -amino -diazocarbonyl
compounds were then investigated (Scheme 2). In the presence
of Rh2(Oct)4, the intramolecular N-H insertion reactions of (-)-2e
proceeded smoothly, delivering the corresponding aziridine
products 4e in 60 yield with e.r. of 90.5:9.5. Amino protection of
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resonance appeared at -73.16, -75.28, -77.17 ppm. After 3
hours, the peaks at -64.85 ppm (from 1g), -73.16 ppm
disappeared and the peak at 75.28 ppm becomes smaller. This
result suggests that -73.16 ppm and -75.28 are most likely the
reaction intermediates. The key reaction intermediates were
then detected by ESI-MS (Fig. 1), which is a direct and reliable
method for the characterization of reaction intermediates in
situ.[12] When the reaction mixed DPPB and TMSN3 in DCM was
monitored, an ion of m/z 542 was obtained (Fig. 1a), indicating
the existence of intermediate IA. The SAESI-MS/MS spectrum
of the reaction mixture of 1g, TMSN3 and PPh3, exhibits the
peak at m/z 612 (Fig. 1b) and m/z 350 (Fig. S7), which support
the structures of intermediates IB or IC and ID.
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Figure 1. ESI-MS studies: a) SAESI-MS spectrum of the reaction solution in
DCM, showing the complex ion [TMSN3(DPPB)+H]+ at m/z 542. b) The
SAESI-MS/MS spectrum of [C31H31ClF3N3OPSi]+ at m/z 612.
In summary, we have developed
a novel strategy for
phosphine-catalyzed difunctionalization of ,-enones under the
mild reaction conditions. In particular, it is the first example of
construction of -diazo carbonyl compounds under phosphine
catalysis conditions. In contrast, the corresponding -azide
compounds would be furnished with the use of ,-disubstituted
enones or 3-aroyl acrylates via the direct monofunctionalization
(azidation) reaction. Furthermore, a preliminary result showed
that an asymmetric variant of the reaction has also been realized
with quite high enantioselectivities with the use of nucleophilic
bifunctional phosphine P4 as a chiral catalyst, which providing a
facile access to various functional fluoroalkylated -amino -
diazocarbonyl compounds. Mechanistic studies shed some light
on the mode of catalyst activation and intermediate formation.
ESI-MS studies were carried out to detect the reaction
intermediates to explain the process.
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Acknowledgements
We are grateful to 973 Programs (2015CB856600), National
Natural Science Foundation of China (21425205) and
Changjiang Scholars and Innovative Research Team in
University (PCSIRT) for financial supports.
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Keywords: phosphine catalysis• alkene difunctionalization•
diazo compounds• azide •enones
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Phosphine-Catalyzed
Difunctionalization of ,-Enones: A
Direct Approach to -Amino -
DiazoCarbonyl Compounds
An efficient and practical phosphine-catalyzed vicinal difunctionalization of -fluoroalkyl ,-
enones with TMSN3 has been developed. Meanwhile, the asymmetry variant induced by the
nucleophilic bifunctional phosphine P4 led to various chiral fluoroalkylated -amino -
diazocarbonyl compounds in high yields and enantioselectivity.
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