Chemodivergent and Stereoselective Construction of gem-Difluoroallylic Amines from Masked Difluorodiazo Reagents

Article abstract of DOI:10.1021/acs.orglett.9b02989

We report a general and efficient approach to construct achiral and chiral gem-difluoroallylic amines from a masked difluorodiazo reagent (PhSO₂CF₂CHN₂) and readily available imines. This facile protocol takes advantage of the phenylsulfonyl and diazo moieties as efficient activating and directing groups to assist difluoroalkyl incorporation and facilitate the chemodivergent and stereoselective formation of gem-difluoroallylic amines.

Full text of DOI:10.1021/acs.orglett.9b02989

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemodivergent and Stereoselective Construction of gem-
Difluoroallylic Amines from Masked Difluorodiazo Reagents
Jun-Liang Zeng,†,‡,∥ Yue Zhang,†,‡,∥ Meng-Meng Zheng,§ Zhi-Qi Zhang,†,‡ Xiao-Song Xue,§
Fa-Guang Zhang,*,†,‡ and Jun-An Ma*,†,‡,§
†Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation
Centre of Chemical Science & Engineering, Tianjin University, Tianjin 300072 P.R. China
‡Joint School of NUS & TJU, International Campus of Tianjin University, Fuzhou 350207, P.R. China
§State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P.R. China
S
* Supporting Information
ABSTRACT: We report a general and efficient approach to construct achiral and chiral gem-difluoroallylic amines from a
masked difluorodiazo reagent (PhSO2CF2CHN2) and readily available imines. This facile protocol takes advantage of the
phenylsulfonyl and diazo moieties as efficient activating and directing groups to assist difluoroalkyl incorporation and facilitate
the chemodivergent and stereoselective formation of gem-difluoroallylic amines.
gem-Difluoroalkenes have emerged as a powerful type of
versatile building block in organic synthesis and drug
discovery.1 As a result, the efficient construction of various
gem-difluoroalkenyl frameworks has attracted remarkably
tremendous attention in the past two decades.2−4 In this
context, gem-difluoroallylic amines have become a new
spotlight and have been found as the core structure in many
bioactive molecules (Figure 1). Despite their increasingly great
desirable and still represents a formidable challenge.6 In this
endeavor, one report by Hu and co-workers has addressed the
nucleophilic ring-opening fluoroalkylation of chiral cyclic
sulfamidates with PhSO2CF2H, thus giving stereospecifically
the enantioenriched gem-difluoroallylic amine after desulfona-
tion, albeit with only one example (Scheme 1a).7 Inspired by
this pioneering study and with our recently developed masked
Scheme 1. Construction of gem-Difluoroallylic Amines from
Difluorinated Nucleophiles
Figure 1. Representative bioactive molecules containing the gem-
difluoroallylic amine motif.
potential, there are surprisingly limited synthetic methods to
gem-difluoroallylic amines compared with other widely
investigated gem-difluoroalkenyl targets. Indeed, conventional
synthetic methods, such as Wittig-type olefinations, often suffer
from harsh reaction conditions, limited substrate scope, and
the requirement of chiral starting materials.5 In particular, a
general approach to access gem-difluoroallylic amines is highly
Received: August 21, 2019
© XXXX American Chemical Society
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Scheme 2. (a) Optimized One-Pot Formation of Enamine 3a from 1 and 2a; (b) Azo-Mannich Reaction of 1 and 2a; (c)
Formation of 3a from 4a; (d) Deuterium-Labeling Experiment; (e) Calculated Free Energy Profile (kcal/mol) for the
( )-BPA-Catalyzed Model Olefination Reaction Using the SMD-M06-2X/6-311+G(d,p)//B3LYP/6-31G(d,p) Method
a
a
The selected bond lengths are in angstroms.
difluorodiazo reagent (PhSO2CF2CHN2) in hand,8 we
envisioned that the corresponding achiral and chiral gem-
difluoroallylic amines could be selectively constructed by
means of a chemodivergent strategy from the same set of
starting materials. In this scenario, the phenylsulfonyl and
diazo moieties would function as potential activating and
directing groups to assist difluoroalkyl incorporation and
ultimately facilitate the formation of gem-difluoroallylic amines
(Scheme 1b). Herein, we report our efforts in developing a
stereoselective one-pot olefination reaction and an enantiose-
lective Mannich-type condensation between PhSO2CF2CHN2
and readily available imines. This facile protocol provides a
general and efficient approach for the preparation of gem-
difluoroallylic amines under mild reaction conditions.
The stepwise process involving the base-mediated Mannich
reaction of diazo compounds with imines and subsequent Rh-
catalyzed decomposition−migration of the diazo-Mannich
adducts to produce β-enamino esters was first reported by
Wang and co-workers.9 Encouraged by this seminal study, we
attempted the one-pot olefination reaction of PhSO2CF2CHN2
1 with phenylaldimine 2a in the presence of various Brønsted
acids (see Table S1). Fortunately, the desired enamine 3a
could be obtained in variable yields. Further condition
optimization showed that the use of BINOL-derived
phosphoric acid [( )-BPA] in DCM delivered the product
3a as a single E isomer in 76% yield (Scheme 2a). It is very
interesting that the addition of TEMPO or K3PO4 into the
reaction system furnished the diazo-Mannich adduct 4a in high
yield (Scheme 2b). As anticipated, when the diazo-Mannich
adduct 4a was treated with ( )-BPA, the corresponding
rearrangement enamine 3a was afforded in 96% yield as a
single isomer (Scheme 2c). When deuterated 4′-chloropheny-
laldimine was prepared and subjected to this one-pot reaction
under identical conditions, the corresponding deuterated
product was obtained with the deuterium atom completely
incorporated at the vinyl position (Scheme 2d). These
preliminary results strongly suggest that (i) the diazo-Mannich
adducts 4 could be the key intermediates leading to the
formation of enamines 3; (ii) the presence of a suitable
Brønsted acid is essential for the rearrangement step, while
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Scheme 3. Scope of Catalytic Chemodivergent and Stereoselective Transformations between Imines 2 and Difluorodiazo
Compound 1
TEMPO or K3PO4 can serve as a powerful interupter by
inhibiting the aryl-migration process of diazo compounds 4 to
enamines 3; and (iii) no cleavage of the imine C−H bonds
occurs during the whole reaction process. In order to delineate
the details of the putative cascade process, preliminary density
functional theory (DFT) calculations using the M06-2X/6-
311+G(d,p)//B3LYP/6-31G(d,p) method were performed
(Scheme 2e).10 The calculations show that the formation of
diazo-Mannich adducts is kinetically favorable, whereas the
generation of final enamine products after the rearrangement
step is thermodynamically preferable. This prediction is
consistent with the experimental results as 4a was obtained
as the major product when the reaction was run at low
temperature (0 °C). The activation free energies for the
nucleophilic addition, aryl migration, and hydrogen transfer are
14.2, 24.5, and 13.2 kcal/mol, respectively. Thus, the rate-
determining step for the whole catalytic cycle could be the 1,2-
aryl migration process (TS3).10 In addition, the computational
results also reveal that the observed stereospecificity of the
rearrangement could originate from the hydrogen transfer at
the same side of amino group controlled by phosphoric acid’s
C
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Scheme 4. Further Desulfonation and/or Diazo-Eliminating Transformations to Achiral and Chiral gem-Difluoroallylic Amines
double hydrogen bonding in a cyclic transition state structure
(TS4).
eoselectivity. Furthermore, alkyl-derived imine was also well
accommodated in this reaction and furnished the correspond-
ing product 4z in decent yield with excellent ee value.
Having established the optimal conditions for this novel
one-pot olefination reaction, an investigation of the substrate
scope was then carried out (Scheme 3, left). Generally, this
transformation is compatible with a variety of aromatic
aldimines with different electronic properties and substitution
patterns, thus providing enamines 3a−3c′ bearing the
difluoromethyl functional group in good to high yields with
exclusive E geometry selectivity. In particular, an electron-
donating group on the phenyl ring is beneficial for this
transformation, as demonstrated by the high yields of 3b−3m.
Phenyl aldimines bearing substituents at para-, meta-, or ortho-
positions on the phenyl ring are all viable substrates (3b−3v).
Notably, the molecular structure and stereoconfiguration of
obtained products are assigned by analogy via X-ray analysis of
the compound 3b′.11 Furthermore, this approach has been
successfully applied to structurally complex substrate, thereby
generating CF2-containing estrone-derived enamine 3c′ in 89%
yield. In addition, no enamine was observed when alkyl imine
was subjected to this transformation, thus verifying the
proposed mechanism involving the aryl-participating rear-
rangement process.
On the other hand, we also attempted to interrupt the
cascade process to afford the enantioenriched diazo-Mannich
adduct 4a from imine 2a and PhSO2CF2CHN2.12 By screening
chiral catalysts and achiral additives (see Table S2), it was
found that the combination of (S)-3,3′-bis(2,4,6-triisopropyl-
phenyl)-BINOL-derived phosphoric acid [(S)-TRIP] with
TEMPO delivered the desired 4a in 98% yield with 94%
ee.11 Subsequently, an evaluation of the substrate scope shows
that a wide range of aldimines could proceed well in this
catalytic enantioselective reaction, thereby giving difluorodia-
zoethyl-substituted amines in moderate to high yields with
excellent enantioselectivities (Scheme 3, right). Aromatic
imines substituted with electron-neutral, electron-donating,
or electron-withdrawing groups at the para-, meta-, or ortho-
positions on the phenyl ring, and all underwent this
transformation smoothly to provide the corresponding chiral
adducts (4a−4s). This organocatalytic transformation is also
well compatible with imine counterparts bearing other
aromatic and heteroaromatic rings, such as 2-naphthyl, 1-
naphthyl, 2-thienyl, and 3-pyridinyl (4t−4x). X-ray crystallo-
graphic analysis of compound 4v allowed the absolute
configuration of the stereogenic center to be assigned as S.11
Interestingly, adding molecular complexity to phenylalanine-
derived imine also proved to be viable, thus delivering
difluorodiazoethyl-containing compound 4y with high diaster-
To demonstrate the synthetic utility of this newly developed
chemodivergent and stereoselective protocol, the SmI2-
promoted desulfonation process was applied for the enamines
3 and the diazo-Mannich adducts 4. As shown in Scheme 4,
both transformations proceed smoothly, thus giving rise to a
broad range of gem-difluoroallylic amines 5a−5g in 64−80%
yields and chiral gem-difluoroallylic amines 6a−6g in 72−93%
yields, respectively. Significantly, compound 5a has been
demonstrated to be a potent inhibitor for the quinone-
dependent bovine plasma amine oxidase (BPAO).5e The
current protocol provides an efficient and alternative approach
to access these useful core structures possessing the gem-
difluoroallylic amine motif. The good generality of the scope is
further exemplified through its smooth application to the
synthesis of potential bioactive estrone-derived compound 5g
in 75% yield. Notably, the enantioenriched gem-difluoroallylic
amines are biologically interesting, yet their asymmetric
construction via conventional methods is still far from trivial.
Thus, aromatic and heteroaromatic substrates substituted with
an electron-donating group, an electron-withdrawing group,
and halogen were probed in a one-pot desulfonation and diazo-
eliminating transformation, delivering the corresponding
products 6b−6e with good results. The alkyl aldimine-derived
Mannich adduct 4z is also well compatible with this reaction
and afforded the chiral gem-difluoroallylic amine 6f in good
yield without any erosion of enantiopurity. Importantly,
phenylalanine derivative 6g bearing the gem-difluoroallylic
amine moiety was also obtained, offering great opportunities
for further biological or medical studies. These results clearly
validate this chemodivergent strategy and demonstrated that
our current protocol takes advantage of the phenylsulfonyl and
diazo moieties as efficient activating and directing groups to
assist difluoroalkyl incorporation and facilitate the stereo-
selective formation of gem-difluoroallylic amines.
In summary, we have successfully developed a general and
efficient method for the construction of both chiral and achiral
gem-difluoroallylic amines via chemodivergent transformations
between a masked difluorodiazo reagent and readily available
aldimines. This facile protocol consists of a stereoselective one-
pot olefination and an enantioselective Mannich-type reaction,
featuring broad substrate scope, operational convenience, and
mild reaction conditions. Further investigations to extend the
substrate scope and other applications are underway in our
laboratory, the results of which will be reported in due course.
D
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02989.
■
S
Experimental procedures, compound characterization
data, computation details, and NMR spectra for new
compounds (PDF)
Accession Codes
CCDC 1852012−1852013 and 1877090 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(5) For the synthesis of gem-difluoroallylic hydrazines via Wittig-type
olefination reactions, see: (a) Nowak, I.; Robins, M. J. Org. Lett. 2005,
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7, 721−724. (b) Podichetty, A. K.; Wagner, S.; Faust, A.; Schafers,
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Ojima, I. J. Fluorine Chem. 2012, 143, 177−188. For the synthesis of
gem-difluoroallylic amines via Mitsunobu reactions, see: (d) Kolb, M.;
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: majun_an68@tju.edu.cn.
*E-mail: zhangfg1987@tju.edu.cn.
ORCID
Jun-Liang Zeng: 0000-0003-2442-8653
Xiao-Song Xue: 0000-0003-4541-8702
Fa-Guang Zhang: 0000-0002-0251-0456
Jun-An Ma: 0000-0002-3902-6799
Author Contributions
∥J.-L.Z. and Y.Z. contributed equally to this work.
Notes
(6) (a) Uneyama, K.; Katagiri, T.; Amii, H. Acc. Chem. Res. 2008, 41,
817−829. (b) Uneyama, K.; Yamazaki, T. J. Fluorine Chem. 2017, 203,
3−30.
(7) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed. 2007, 46,
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(8) (a) Zeng, J.-L.; Chen, Z.; Zhang, F.-G.; Ma, J.-A. Org. Lett. 2018,
20, 4562−4565. (b) Ma, J.-A.; Zeng, J.-L.; Zhang, F.-G. China Patent
CN 108383761A, 2018. For a review on difluorinated diazo
compounds, see: (c) Mykhailiuk, P. K.; Koenigs, R. M. Chem. - Eur. J.
2019, 25, 6053−6063.
(9) (a) Jiang, N.; Qu, Z.; Wang, J. Org. Lett. 2001, 3, 2989−2992.
(b) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.; Wang, J. J. Org. Chem.
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(10) The tert-butyl group of imine 2a was simplified to a methyl
group during computational studies. Buta-1,3-diene-1,4-diol−phos-
phoric acid was used as a model for the BINOL-derived phosphoric
acid catalyst during computational studies. Alternatively, the 1,2-H
migration pathway was also investigated and resulted in an energy
barrier of 29.2 kcal/mol, which is in line with the experimental result
that the 1,2-phenyl migration product was solely observed. See the
Supporting Information for more information.
(11) To further understand the role of TEMPO in the Mannich-type
reaction, the mixture of ( )-BPA and TEMPO was crystallized and
subjected to X-ray structural analysis. It showed that the Brønsted
acid has been changed to a new tight ion-pairing complex BPT
possessing noncovalent interaction between phosphoric acid and the
nitroxide via O−···H−N+ association. The distance of O−···H is
determined to be 1.78 Å, and the angle of O−···H−N+ is determined
to be 176.1°, indicating the existence of a hydrogen bond with
moderate strength. This result clearly demonstrates the essential role
of TEMPO in inhabiting the aryl-migration process by changing the
Brønsted acidity of phosphoric acid.
(12) For a review on asymmetric diazo-Mannich reactions, see:
(a) Zhang, Y.; Wang, J. Chem. Commun. 2009, 5350−5361. For
selected examples, see: (b) Zhao, Y.; Ma, Z.; Zhang, X.; Zou, Y.; Jin,
X.; Wang, J. Angew. Chem., Int. Ed. 2004, 43, 5977−5980.
(c) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
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Soc. 2007, 129, 10054−10055. (e) Hashimoto, T.; Maruoka, K.
Synthesis 2008, 2008, 3703−3706. (f) Hashimoto, T.; Kimura, H.;
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21532008, 21772142, 21901181,
and 21971186) and Tianjin Municipal Science & Technology
Commission (19JCQNJC04700). We thank Long Sun of
Changzhi University for help with X-ray crystallography.
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