II. Enantioselective Synthesis of β-Amino-α-Fluoronitroalkanes via the Aza-Henry
2.3 Synthesis and Application of Fluoronitroalkanes
aryl fluorides, yet much less is reported to make alkyl fluorides, especially in asymmetric fashion. Metal salen catalysts pioneered by Jacobsen have been the most successful in this realm, specifically in the fluoride ring openings of epoxides (111)94 and aziridines (115).95 The kinetic resolutions of racemic and meso-epoxides yielding enantioenriched β-fluoro alcohols (112) have garnered more attention lately using fluoride sources such as silver fluoride (AgF), HF (generated in situ from benzoyl fluoride), or Et3NHF (or equivalents). Doyle and coworkers in particular have found success using benzoyl fluoride and the cobalt(III) salen catalyst 113 in the kinetic resolutions of various rac-epoxides and protected meso-aziridines (Scheme 28).
reactivity of such a small, reactive, and capricious atom is far form facile. A number of new catalysts, activation methods, and general understanding of its behaviors is at the very least required. In regard to atom economy96 and the green nature of these reactions, current standards for delivering a fluorine atom in asymmetric fashion fall short. State-of-the-art enantioselective fluorinations require a large molecular weight reagents and catalysts – the latter of which are complex, non C2-symmetric, metal-based complexes that require many steps to prepare.
Additionally, the fluorinating reagents employed, while useful, are also high molecular weight species, all to deliver a single fluorine atom (i.e., Selectfluor MW: 354.26) – this observation is depicted in Scheme 29. Various additives, organic/inorganic bases, Lewis acids, and detailed solvent combinations are often needed to obtain desired reactivity or stereoselection. In union with these constraints, the complexity of the final fluorinated product – is often just that – fluorinated. Presently and in contrast to the swaths of asymmetric carbon-carbon bond forming reactions, little if any additional stereocenters are created in current asymmetric monofluorination reactions. Furthermore, new hetero- or carbon atoms are often not introduced, which would add desirability and more complexity to these methods while creating a more diverse class of chemicals.
96 Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259.
Scheme 30. Applications of fluoronitroalkanes in asymmetric catalysis. The products may contain stereocenters.
R NO2 F R
OH F R NO2
R HN
F R NO2 PG
F R NO2 R
X
F R NO2 R
R X
*
*
* *
* *
* *
Michael Acceptors Henry Reaction
Aza-Henry Reaction
Ring-Openings
As discussed in Chapter 1, nitroalkanes are tremendously useful pronucleophiles used in a myriad of asymmetric transformations and subsequent derivatizations. The synthesis of fluoronitroalkanes, whilst not new, has reentered mainstream organic synthesis in the past few years. A report from Kornblum in 1956 prepared the first fluoronitroalkane using harsh conditions (F2, high temps) but recent advances in fluorination chemistry have allowed for using more mild conditions.
The implementation of these dynamic pronucleophiles have a number of attractive characteristics: they are 1) readily isolable and stable solids or oils, 2) their relative low acidity is amenable to numerous and mild Brønsted basic catalysts (chiral and achiral), 3) they can conceivable be used with any electrophile (carbonyls, imines, activated olefins, etc.), 4) high atom economy (all atoms from substrate are contained in the product), and 5) they may introduce diverse functionalities centered around the fluorine atom, the products of which bear chiral centers (Scheme 30). It’s for these reasons that this class of pronucleophiles offers exciting and intriguing reagent alternatives to fluoronium (F+) or fluoride (F–) sources, while retaining the potential to capitalize on stereochemical induction.
Treating a variety of nitroalkanes (aryl nitromethanes and aliphatic nitroalkanes) with
Scheme 31. State-of-the-art synthesis of fluoronitroalkanes. A recent example detailing the synthesis of racemic Henry products.
CH3CN/H2O i) KOH
R NO2 R NO2
ii) Selectfluor in DCM F
0 °C to -20 °C
to 10 °C > 60% yields
THF R
F 30 mol % TMG
from -30 °C to RT
47-81% yield R2 H
O R1 NO2
F
NO2 OH R
117 117
117 118
KOH and quenching the nitronate with Selectfluor generates fluoronitroalkanes 117 (>95%
monofluorination) in good yields (Scheme 31).97 α-Fluoronitroesters were the earliest fluoronitroalkane pronucleophiles to be employed in addition chemistry (to a Michael acceptor),98 but the Henry reaction using TMG as the base to generate racemic α-oxy fluoronitroalkanes (118) was reported soon after.97 Koizumi in the early 1980’s was the first to generally explore fluoronitroalkanes and fluoronitroesters and their utility, yet since then, substantial progress has not been made.
Asymmetric, organocatalyzed reactions using these fluorinated pronucleophiles have more recently been reported. The Lu group from the University of Singapore published a pair of asymmetric reactions using fluoronitroalkanes and fluoronitroesters – nitro olefins were
97 Hu, H. W.; Huang, Y. G.; Guo, Y. J. Fluorine Chem 2012, 133, 108.
98 Cui, H. P.; Li, P.; Wang, X. W.; Chai, Z.; Yang, Y. Q.; Cai, Y. P.; Zhu, S. Z.; Zhao, G. Tetrahedron 2011, 67, 312.
Scheme 32. Seminal report from Lu describing the asymmetric, organocatalyzed addition of aryl fluoronitromethanes to nitro olefins and subsequent sample of reaction scope.
N
N H
NH O
HN
Me TBDPSO
HN
S toluene, 48 h
10 mol % thiourea 121
0 °C R2
R1 NO2 F
NO2
R1 F O2N
R2 NO2
CF3 CF3
F O2N
Ph NO2 NC
F O2N
Ph NO2 Cl
Ph F O2N
NO2
CF3 Ph
F O2N
NO2 F
F O2N
Me 85% yield
6:1 dr, 88% ee
84% yield 7:1 dr, 87% ee
75% yield 5:1 dr, 91% ee 76% yield
5:1 dr, 85% ee
NO2 Me
95% yield 6:1 dr, 82% ee NC
thiourea 121
sample of scope
122 119
117 120
employed as the electrophiles in both cases (Scheme 32).
Their first report described the enantioselective addition of aryl nitromethanes 117 to nitro olefins 119 in good levels of ee using quinidine- and quinine-derived organocatalysts.99 The optimal catalyst in this work, quinine-derived catalyst 121, interestingly included an appended enantioenriched amino acid, generating the threonine-OTBDPS thiourea. Use of 10 mol % catalyst loading in toluene at 0 °C afforded the product in 5:1 dr, 90% ee, and 82 % yield.
The substrate scope here was reasonably broad, including electronically-diverse aryl nitro olefins, a heteroaromatic example, and a couple of alkyl nitro olefins, although the adducts of the latter electrophiles were isolated in lower ee (122, 82% ee, Scheme 32). Diastereoselection was not generally high, up to 8:1 dr in the best cases. Notably and quite perplexing, aliphatic fluoronitroalkanes were not tolerated under this quinine-thiourea catalytic system – the authors do not speculate why this is the case.
After “much experimentation” the authors were able to selectively reduce the nitro group of 123 to the Boc-protected amine 124 using Lindlar’s catalyst (Pa/BaSO4) and 15 atm H2, although only in 23% isolated yield (Scheme 33). The great challenge is the elimination of fluoride (F–) once a lone-pair is freed on the α-heteroatom – Koizumi and others theorized the α-
99 Kwiatkowski, J.; Lu, Y. X. Chem. Commun. 2014, 50, 9313.
Scheme 33. Reductive hydrogenation of α-fluoronitroalkanes using Lindlar’s catalyst.
MeOH, MS 4A H2 (15 atm)
RT, 2d
Ph F NH
Ph NHBoc Ph
F O2N
Ph NO2
Pd/BaSO4 (5 mol %) Boc Boc2O, AcOH (cat.)
(23%) 5:1 dr
123 124
fluoroamine motif (broadly) is highly unstable in nature and may not exist for any extended period of time.100
The next report from Lu used α-fluoro-α-nitro acetates 125 in an extension of this asymmetric, organocatalyzed addition to nitro olefins 119.101 The same quinine-based thiourea catalyst 121 was used in this work as well, generating the α-fluoro-α,δ-dinitro esters in moderate to good ee but generally very low dr (up to 3:1 dr; Scheme 34). The electronics of the aryl nitro olefin coupling partner had more of a dramatic effect on ee in this work, potentially due to the more reactive (or Brønsted acidic) nucleophile being employed.
100 Takeuchi, Y.; Takagi, K.; Yamaba, T.; Nabetani, M.; Koizumi, T. J. Fluorine Chem 1994, 68, 149. Annedi, S. C.;
Li, W.; Samson, S.; Kotra, L. P. J. Org. Chem. 2003, 68, 1043.
101 Kwiatkowski, J.; Lu, Y. X. Org. Biomol. Chem. 2015, 13, 2350.
Scheme 34. Lu’s report employing α-fluoronitro acetates 125 in the enantioselective addition into nitro olefins and a sample of the reaction scope.
toluene, 3 h 10 mol % thiourea 121
0 °C R2
EtO2C NO2 F
NO2
EtO2C F O2N
R2 NO2
CO2Et F NO2
NO2
CO2Et F NO2
NO2 F
CO2Et F NO2
NO2 MeO
MeO
CO2Et F NO2
NO2
90% yield 3:2 dr, 81% ee
95% yield 2:1 dr, 85% ee 97% yield
3:1 dr, 82% ee
94% yield 3:2 dr, 63% ee sample of scope
125 119 126
Scheme 35. Reductive hydrogenation of the nitro group to the Boc-amine 128 using Lindlar’s catalysts again results in low yields.
MeOH, MS 4A H2 (6 atm)
RT, 12 h Pd/BaSO4 (3 mol %)
Boc2O, AcOH (cat.)
(20%)
CO2Et F NHBoc Ph
NHBoc CO2Et
F NO2 Ph
NO2
3:1 dr
127 128
In an effort to generate α-fluoro amino acid derivatives, the authors again struggled with the reduction of the nitro group to the protected amine 128 (Scheme 35). Yields were similarly very low (20%) using Lindlar’s catalyst (Pa/BaSO4, 6 atm H2) but they were able to obtain the desired amino acid derivative 128 in low dr (3:1 dr). In sum, the chemistry of these α- fluoronitroalkane products is promising, yet much work is needed to truly explore the potential and synthetic applications.