High-valent palladium-promoted formal Wagner-Meerwein rearrangement

Article abstract of DOI:10.1021/acs.orglett.6b02706

An oxy-palladation, formal Wagner-Meerwein rearrangement and fluorination cascade has been established for generating fluorinated oxazolidine-2,4-diones and oxazolidin-2-ones. The reaction has a broad substrate scope in which both aryl and alkyl groups can be utilized as efficient migrating groups. Experimental evidence suggests that the reaction is initiated by anti-oxy-palladation of the olefin, followed by oxidative generation of an alkyl Pd^IV intermediate and a concerted migration-fluorination.

Full text of DOI:10.1021/acs.orglett.6b02706

Letter
pubs.acs.org/OrgLett
High-Valent Palladium-Promoted Formal Wagner−Meerwein
Rearrangement
Hongmiao Wu,† Bin Yang,† Lin Zhu,† Ronghua Lu,† Guigen Li,*,†,‡ and Hongjian Lu*,†
†Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210093, P. R. China
‡Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States
S
* Supporting Information
ABSTRACT: An oxy-palladation, formal Wagner−Meerwein rearrangement and fluorination cascade has been established for
generating fluorinated oxazolidine-2,4-diones and oxazolidin-2-ones. The reaction has a broad substrate scope in which both aryl
and alkyl groups can be utilized as efficient migrating groups. Experimental evidence suggests that the reaction is initiated by anti-
oxy-palladation of the olefin, followed by oxidative generation of an alkyl PdIV intermediate and a concerted migration−fluorination.
produce ring-expanded ketone product in good yield. Also, in an
he Wacker process, reported in 1959, inspired an era
Tof research in palladium catalysis which demonstrated isolated case, 1,1-diphenylethylene undergoes a similar migration
the powerful utility of Pd0/PdII catalysis in organometallic
process benefiting from the anchimeric assistance to produce
benzyl phenyl ketone in low yield.9,10 No further study on
this topic has been subsequently reported probably due to the
intrinsic limitation of Pd0/PdII catalytic efficiency.
chemistry.1 In the past decade, processes mediated by high-
valent palladium2 have emerged as flexible protocols that com-
plement the traditional low-valent reactions. Benefiting from the
fundamental studies on high-valent palladium complexes, the
enhanced reductive elimination3,4 and inhibited β-elimination
features5 are now well understood and have been widely applied
to a number of challenging reactions, such as the formation of
C−halogen (heavy),6 C−F,7 and C−CF38 bonds.
We speculated that under strong oxidative conditions
(PdII/PdIV cycle, Scheme 1) the Wacker intermediate A could
be converted to the PdIV intermediate B. The enhanced posi-
tive charge at the α-carbon to palladium would facilitate the
Wagner−Meerwein-type migration process and allow more
efficient migration of versatile Rm groups without the additional
driving force gained by releasing strained rings or anchimeric
assistance. The challenges lie in the competition with the facile
reductive elimination pathway of the PdIV complex, which
has been demonstrated frequently in olefin difunctionalization
reactions11 and the potential C−H activation pathways involving
PdIV intermediates.12
To our delight, compound 1a with a phenyl ring as the
migrating group did react as anticipated with Pd(OAc)2 as
catalyst and Selectfluor (F-1) as oxidant in acetonitrile (Table 1).
Fluorination occurred following the migration, providing com-
pound 2a in 70% yield. The structure was confirmed unambi-
gously by X-ray analysis. The direct C−F reductive elimination
process was successfully suppressed to produce the regioisomer
2a′ in a 2a′/2a ratio of 1/13 (entry 1). PdCl2, Pd(OTFA)2, or
Pd(OPiv)2 provided either diminished yield or poor selectivity
(entries 2−4). Neither 2a nor 2a′ is observed in the absence
A survey of the literature on palladium chemistry reveals an
interesting variation of the Wacker process, the Pd0/PdII cycle
(Scheme 1).9 For the olefin substrate containing a strained ring,
the Wacker intermediate A undergoes a 1,2-migration process to
Scheme 1. Formal Wagner−Meerwein Rearrangement in
Wacker−Tsuji Oxidation
Received: September 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02706
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Organic Letters
Letter
a
Table 1. Selected Results of Condition Optimization
Scheme 2. Substrate Scope of Activated Olefin
a
Reaction conditions: substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol %),
b
Selectfluor (1.3 equiv), MeCN (2 mL), 35 °C, 24 h. Isolated yield of
2, ratio of 2:2′ given in parentheses as determined by 19FNMR or
1HNMR analysis of the crude products. des-Boc product and poly-
c
merization product were responsible for the low yield. Diastereomeric
d
e
ratio 50/50. Diastereomeric ratio 65/35. Diastereomeric ratio 79/21.
f
Reaction was conducted at 50 °C.
a
Standard conditions: substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol %),
also performed well in this process. The scope of migrating group
Rm was also investigated (Scheme 2). Encouragingly, ethyl (2o),
benzyl (2q), octyl (2r), and even cyclopropylmethylene (2s)
groups all migrate efficiently, producing the isomeric difunction-
b
Selectfluor (1.3 equiv), MeCN (2 mL), 35 °C, 24 h. NMR yield with
N,N′-dimethylacetamide as internal standard; ratio of 2:2′ is given in
c
d
parentheses. Isolated yield of compound 2. Starting material 1a was
e
f
recovered. L-1, L-2, L-3, and L-4 were screened. F-2, F-3, and F-4
were screened. A combination of 1 equiv of PhI(OAc)2 and 1 equiv of
AgF (or CsF) was screened. DCM, water, EtOH, EtOAc, MeNO2,
and DMF were screened.
i
alized products. But the bulkier Pr migrating group gave a
g
significantly lower yield (2p). Aryl migrating groups were also
examined (2a,t−y) and led to considerably reduced yields
resulting from formation of byproduct 2′. This pathway was
attributed not only to the direct C−F reductive elimination
but also to the regioselectivity associated with the nucleophilic
opening of the phenonium intermediate,13 showing the signifi-
cant dependence on the electronic nature of the aryl migrating
groups. Electron-donating substituents, such as methyl (2t,v),
methoxyl (2u), and the π-electron-donating 4-fluoro (2w)
group, gave diminished regioselectivity, while electron-with-
drawing substituents, such as COOEt (2x) and CHO (2y)
groups at the para-position, resulted in high regioselectivity.
Instead of tert-butyl carbamates, isopropyl methacryloyl-
(phenyl)carbamate was used as the substrate, and the yield of
2b dropped to 55%.
During the investigation, we found that compound 3a, an
unactivated olefin, was also compatible with this catalytic system
to afford product 4a in 58% yield with excellent regioselectivity
with respect to 4a′ (Scheme 3). This is particularly interesting
because a background reaction exists without Pd catalyst, which
leads to the formation of 4a′ predominantly.14 A brief investi-
gation of substrate 3 was conducted (Scheme 3). A lower yield
was obtained with 2-ethylphenyl substituents on nitrogen (4b).
Phenyl rings with electron-withdrawing groups, such as
4-nitro (4c), 4-CN (4d), and perfluoro (4e) groups, all provided
acceptable yields. Ts and Boc substituents were also tolerated
well under the present catalytic system (4f,g). Further investiga-
tion showed that ethyl (4h) and benzyl (4i) groups are efficient
migrating groups, affording the products in slightly lower yields.
A phenyl migrating group led to poor regioselectivity due to the
h
of the Pd catalyst (entry 5). A control experiment with a
stoichiometric quantity of the Pd catalyst and no oxidant resulted
in almost no reaction apart from slight decomposition of the Boc
group (entry 6). It indicates that a Pd0/PdII catalytic cycle is
unlikely to work. Common N-σ-donor ligands such as pyridine
and oxazoline derivatives basically inhibit the reaction (entry 7).
When the oxidant is changed from Selectfluor to NFSI (F-2), a
fluoropyridinium reagent (F-3), an iodonium reagent (F-4), or
PhI(OAc)2 with fluorine anion produced only a trace amount of
product 2a (entry 8). Solvent screening showed that acetonitrile
was the only solvent that could efficiently facilitate this reaction
(entry 9). Surprisingly, we found that a methyl group, which
cannot participate in anchimeric assistance, can migrate in the
reaction to produce the target product with even higher yield
(78% yield, entry 10).
Encouraged by these results, we sought to investigate the
scope of substrates. As shown in Scheme 2, variously substituted
phenyl groups on nitrogen were examined (2b−l). Both
electron-donating and -withdrawing groups were well tolerated,
giving good to high yields. A wide range of functional groups
were compatible with this reaction, such as halogens (2f,g,j),
an ester (2k), and a nitro group (2l). Interestingly, bulky sub-
stituents at the ortho position of the phenyl ring resulted in
limited rotation of the aryl C−N bond, which led to the axial
chirality. Diastereomers were observed for substrates with o-ethyl
(2c), o-methoxyl (2d), and o-tert-butyl (2e) groups on the
phenyl ring. In addition to the aryl groups, alkyl groups (2m,n)
B
DOI: 10.1021/acs.orglett.6b02706
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Letter
a
unambiguously by X-ray structural analysis (see the Supporting
Information (SI)), shows that an anti-oxy-palladation18 followed
by C−F bond-forming reductive elimination with retention of
configuration is operating in the reaction.19
Scheme 3. Substrate Scope of Unactivated Olefin
In order to reveal some details of the catalytic mechanism, CD3
substituted compound 1b-D3 was prepared and examined, show-
ing that the CD3 group migrated. In addition, when competitive
experiments of 1a vs 1i and 1a vs 1v were conducted, no
scrambling was observed (Schemes S14 and S15).
On the basis of these results, a working mechanism for
the reaction is proposed in Scheme 5. First, coordination of the
Scheme 5. Proposed Mechanisms for the Isomeric
Difunctionalization Reaction
a
Reaction conditions: substrate 3 (0.1 mmol), Pd(OAc)2 (10 mol %),
b
Selectfluor (2.0 equiv), MeCN (2 mL), rt, 24 h. Isolated yield
of 4. Ratio of 4:4′ was given in parentheses and was determined by
19F NMR analysis. des-Boc product and polymerization product were
c
responsible for the low yield. Reaction was conducted at 0 °C for 24 h
then at rt for 24 h.
strong background reaction in the absence of Pd catalyst (4j).14
In addition, when a homoallylic amine derivative, such as
tert-butyl (3-methylbut-3-en-1-yl) phenylcarbamate, was used as
substrate, no desired 6-membered cyclic product was observed.
Substrate 3k, containing an aryl ring and a methyl substituent,
both of which are potential migrating groups, afforded com-
pound 4k as the major product.15 Compound 4k′ was observed
as the major byproduct, but no methyl migration product was
detected. This result suggested that migration of the phenyl
group is much more favorable than migration of the methyl
group.16 The lower yields observed for substrates with aryl
migrating groups are probably due to side reactions.
substrate to the palladium catalyst generates a PdII complex
(III).20 Then oxy-palladation and oxidation probably occurred to
generate a possible key PdIV intermediate (IV). The enhanced
positive charge at the α-carbon to palladium may induce the
Wagner−Meerwein rearrangement-type migration.21 Trapping
of the resulting intermediate (V) with a fluorine anion22 pro-
duces the final product (2b) (path a). Alternatively, a concerted
migration−fluorination process furnishing the catalytic cycle
could also be envisaged (path b). Although the β-carbon elimi-
nation mechanism is thought to proceed in the Pd0/PdII catalytic
cycle, it is usually suppressed in PdIV complexes (path c).5,23
To probe the possibility of the existence of the two pathways
(paths a and b) after the formation of intermediate IV, deu-
terated substrate (Z)-1b-D was prepared and subjected to the
catalysis (eq 1). The resulting compound 2b-D was observed
The major reaction pathway varies with different substrates
(Scheme 4). For example, the reaction with substrate 5 could
Scheme 4. Substrate-Controlled Reaction Pathways
with a diastereomeric ratio of 78:22 and no H−D scrambling. It is
very likely that both pathways are competing and the concerted
process is dominant (path b). Otherwise, the alternative stepwise
pathway (path a) via intermediate V-D would presumably result
in a significant loss of stereochemical information from the com-
plex IV-D. The configuration of the major diastereomer was
determined by NMR analysis and is in accord with the structure
assigned from mechanism analysis (see the SI).
In summary, an oxy-palladation and formal Wagner−Meerwein
rearrangement cascade has been discovered and can be used
for the construction of fluorinated oxazolidine-2,4-diones and
oxazolidine-2-ones. Both aryl and alkyl groups were found to be
capable of migration during the catalytic process. The reaction is
afford a spiro compound (6) via a C−H activation pathway
(Scheme 4a).17 With substrate 7, a direct C−F reductive
elimination product (8) (Scheme 4b) was isolated as the major
product along with some β-hydrogen elimination byproduct (9).
Both of these examples were rationalized in terms of the
formation of a common PdIV intermediate. Kinetic issues are
probably the reason for the different reaction pathways: for com-
pound 5, an intramolecular 6-membered-ring C−H activation
is more likely to occur; for compound 7, the positive charge
stability and steric hindrance at α-carbon in intermediate I slow
down the migration process leading to the direct reductive
elimination product. The configuration of compound 8, assigned
C
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Organic Letters
Letter
proposed to occur through a PdII/PdIV catalytic cycle involving a
concerted migration−fluorination process to furnish the final
product. Further mechanistic research is in progress by our group
to examine details of the reaction.
16354. (c) Yuan, Z.; Wang, H.; Mu, X.; Chen, P.; Guo, Y.; Liu, G. J. Am.
Chem. Soc. 2015, 137, 2468. (d) He, Y.; Yang, Z.; Thornbury, R. T.;
Toste, F. D. J. Am. Chem. Soc. 2015, 137, 12207.
(8) For selected C−CF3 bond constructions via high-valent palladium
catalysis, see: (a) Mu, X.; Wu, T.; Wang, H.; Guo, Y.; Liu, G. J. Am.
Chem. Soc. 2012, 134, 878. (b) Zhang, L.; Chen, K.; Chen, G.; Li, B.;
Luo, S.; Guo, Q.; Wei, J.; Shi, Z. Org. Lett. 2013, 15, 10.
(9) Boontanonda, P.; Grigg, R. J. Chem. Soc., Chem. Commun. 1977, 583.
(10) For selected examples of the anchimeric assistance of the phenyl
group in Wagner−Meerwein rearrangement, see: (a) Cram, D. J. J. Am.
Chem. Soc. 1949, 71, 3863. (b) Geary, G. C.; Hope, E. G.; Stuart, A. M.
Angew. Chem., Int. Ed. 2015, 54, 14911.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02706.
Detailed experimental procedures and characterization
data for all new compounds (PDF)
X-ray data for compound 2a (CIF)
(11) See ref 2d−f and references cited therein.
(12) For selected reports of C−H activation at PdIV, see: (a) Hull, K.
L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047.
(b) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.; Michael, F. E. J. Am.
Chem. Soc. 2009, 131, 9488. (c) Wang, X.; Leow, D.; Yu, J. Q. J. Am.
Chem. Soc. 2011, 133, 13864. For a recent review, see ref 2a.
(13) Compounds 2a and 2a′ were also speculated to form via a
pathway in Scheme S16 in the SI, see (a) Ilchenko, N. O.; Tasch, B. O.;
X-ray data for compound 8 (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: guigenli@nju.edu.cn.
*E-mail: hongjianlu@nju.edu.cn.
Notes
́
Szabo, K. J. Angew. Chem., Int. Ed. 2014, 53, 12897. (b) Reference 10b.
(14) When substrate 3a or 3j was subjected to the control experiment in
the absence of Pd catalyst, product 4a′ (36%) or 4j′ (77%) was obtained
as the major product along with some polymerization products.
(15) A similar reaction involving different conditions was reported
The authors declare no competing financial interest.
recently; see: Ulmer, A.; Brunner, C.; Arnold, A. M.; Pothig, A.; Gulder,
T. Chem. - Eur. J. 2016, 22, 3660.
̈
ACKNOWLEDGMENTS
■
We are grateful for financial support bythe National Natural
Science Foundation ofChina (21332005, 21472085) and program
A for outstanding PhD candidates of Nanjing University.
(16) For selected examples, see: (a) Winstein, S.; Morse, B. K.;
Grunwald, E.; Schreiber, K. C.; Corse, J. J. Am. Chem. Soc. 1952, 74,
1113. (b) Brown, H. C.; Kim, C. J. J. Am. Chem. Soc. 1968, 90, 2082. In
some cases, 1,2-alkyl shift was more favorable over 1,2-aryl shift to form a
́
́
more stable carbocation transition state, see: (c) Gutierrez-Bonet, A.;
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(19) Previous reports showed that configurational retention of C−F
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during the process, which causes the decline of ee or dr values;
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(20) Substrate 1a with stoichiometric Pd(OAc)2 in the absence of
Selectfluor resulted almost no reaction (Table 1, entry 6). It suggests the
tBu group leaving should occur after the oxidation step.
(21) The migration should proceed anti-periplanar to metal, analogous
́
́
to the Baeyer−Villiger reaction: (a) Cardenas, R.; Cetina, R.; Lagunez-
Otero, J.; Reyes, L. J. Phys. Chem. A 1997, 101, 192. (b) Okuno, Y. Chem.
- Eur. J. 1997, 3, 212.
(22) The fluorine source may also come from the BF4− counteranion;
see ref 13a.
(23) As far as we know, β-alkyl elimination without an additional
driving force (such as ring strain release) has never been reported for
transition-metal complexes. For relative reviews involving the topic of
transition-metal-mediated β-carbon elimination, see: (a) (a) Jun, C.-H.
Chem. Soc. Rev. 2004, 33, 610. (b) Ruhland, K. Eur. J. Org. Chem. 2012,
2012, 2683. Even for the Wacker process (hydrogen shift), evidence
shows the migration proceeds via 1,2-hydride shift-type mechanism
instead of β-H elimination. See: (c) Mimoun, H.; Charpentier, R.;
Mitschler, A.; Fischer, J.; Weiss, R. J. Am. Chem. Soc. 1980, 102, 1047.
(d) Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 2796.
Moreover, the evidence that the cyclopropylmethylene group is also able
to migrate without decomposition further excludes this process
(Scheme 2, substrate 1s).
(7) For selected C−F bond constructions via high-valent palladium
catalysis, see: (a) Wang, X. S.; Mei, T. S.; Yu, J. Q. J. Am. Chem. Soc. 2009,
131, 7520. (b) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131,
D
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Org. Lett. XXXX, XXX, XXX−XXX