Ruthenium catalyzed reductive coupling of paraformaldehyde to trifluoromethyl allenes: CF3-bearing all-carbon quaternary centers

Article abstract of DOI:10.1021/ol401771a

Trifluoromethyl substituted allenes engage in ruthenium catalyzed reductive couplings with paraformaldehyde to form products of hydrohydroxymethylation as single regioisomers. This method enables generation of CF₃-bearing all-carbon quaternary

Full text of DOI:10.1021/ol401771a

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Ruthenium Catalyzed Reductive Coupling
of Paraformaldehyde to Trifluoromethyl
Allenes: CF3‑Bearing All-Carbon
Quaternary Centers
Brannon Sam, T. Patrick Montgomery, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin,
Texas 78712, United States
mkrische@mail.utexas.edu
Received June 22, 2013
ABSTRACT
Trifluoromethyl substituted allenes engage in ruthenium catalyzed reductive couplings with paraformaldehyde to form products of
hydrohydroxymethylation as single regioisomers. This method enables generation of CF3-bearing all-carbon quaternary stereocenters.
Alkene hydroformylation can be performed in an effi-
cient and regioselective manner and represents the largest
volume application of homogeneous metal catalysis.1
Although significant progress toward the hydroformyla-
tion of other π-unsaturated reactants has been made
(dienes,2 alkynes,3 allenes4), incomplete regioselectivities
and “over-hydroformylation” to form dialdehyde products
is often problematic. Alcohol mediated reductive couplings5
of paraformaldehyde to allenes,6a alkynes,6c and dienes,6b,d
which form related products of hydrohydroxymethylation,
provide an alternative to hydroformylation wherein alter-
nate regioisomers are efficiently partitioned through the use
of ruthenium and nickel catalysts.6bÀd To advance this
emergent technology further, a study of the reductive
coupling of CF3-substituted allenes to paraformaldehyde
was undertaken.6a Here, we report a ruthenium catalyzed
reductive coupling of paraformaldehyde to CF3-substituted
allenes that displays complete levels of branched regioselec-
tivity, thus delivering all-carbon quaternary stereocenters
bearing CF3 groups.7À9
(1) For selected reviews on hydroformylation, see: (a) Weissermel,
K.; Arpe, H. J. Industrial Organic Chemistry; Wiley-VCH: Weinheim,
2003; p 127. (b) Rhodium Catalyzed Hydroformylation; van Leeuwen, P.
W. N. M., Claver, C., Eds.; Kluwer Academic Publishers: Dordrecht, Nether-
lands, 2000. (c) Breit, B.; Seiche, W. Synthesis 2001, 1. (d) Kalck, P.; Peres,
Y.; Jenck, J. Adv. Organomet. Chem. 1991, 32, 121. (e) Franke, R.;
€
Selent, D.; Borner, A. Chem. Rev. 2012, 112, 5675.
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Doyama, K.; Joh, T.; Takahashi, S.; Shiohara, T. Tetrahedron Lett.
1986, 27, 4497. (b) Johnson, J. R.; Cuny, G. D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 1995, 34, 1760. (c) Ishii, Y.; Miyashita, K.; Kamita, K.;
Hidai, M. J. Am. Chem. Soc. 1997, 119, 6448. (d) Van den Hoven, B. G.;
Alper, H. J. Org. Chem. 1999, 64, 2964. (e) Van den Hoven, B. G.; Alper,
H. J. Org. Chem. 1999, 64, 9640. (f) Agabekov, V.; Seiche, W.; Breit, B.
Chem. Sci. 2013, 4, 2418. (g) Fang, X.; Zhang, M.; Jackstell, R.; Beller,
M. Angew. Chem., Int. Ed. 2013, 52, 4645.
(4) For selected examples of allene hydroformylation, see: (a) Fell, B.;
Beutler, M. Erdo€l & Kohle, Erdgas 1976, 29, 149. (b) Guo, H.; Ma, S.
Adv. Synth. Catal. 2008, 350, 1213.
(5) For selected reviews on CÀC bond forming hydrogenation and
transfer hydrogenation, see: (a) Bower, J. F.; Krische, M. J. Top.
Organomet. Chem. 2011, 43, 107. (b) Hassan, A.; Krische, M. J. Org.
Process Res. Dev. 2011, 15, 1236. (c) Moran, J.; Krische, M. J. Pure Appl.
Chem. 2012, 84, 1729.
(2) For selected examples of conjugated diene hydroformylation, see:
(a) Clement, W. H.; Orchin, M. Ind. Eng. Chem. Prod. Res. Dev. 1965, 4,
283. (b) Fell, B.; Bahrmann, H. J. Mol. Catal. 1977, 2, 211. (c)
Bahrmann, H.; Fell, B. J. Mol. Catal. 1980, 8, 329. (d) Botteghi, C.;
Branca, M.; Saba, A. J. Organomet. Chem. 1980, 184, C17. (e) van
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r
10.1021/ol401771a
XXXX American Chemical Society

Scheme 1. Synthesis of CF3-Substituted Allenes 5aÀ5fa
Table 1. Selected Optimization Experiments in the Ruthenium
Catalyzed Reductive Coupling of CF3-Substituted Allene 5a
and Paraformaldehydea
entry
[Ru]
ligand
yield %
6a:7a
RuBr(CO)3(B3-C3H5)
RuH2(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuTFA2(CO)(PPh3)2
RuTFA2(CO)(PPh3)2
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
RuHCl(CO)(PPh3)3
t-BuPPh2
À
12
18
37
41
40
68
37
58
74
78
70
35
70
68
67
31
20:1
>20:1
12:1
13:1
1:4
b
1
2
3
À
4
À
5
DPPF
DPPF
DiPPF
DtBPF
DPPM
DPPM
DPPE
DPPP
DPPB
DCyPM
DCyPE
BINAP
6
12:1
>20:1
>20:1
20:1
20:1
9:1
7
8
9
10
11
12
13
14
15
16
3:1
1:4
10:1
17:1
10:1
a Yields are of material isolated by silica gel chromatography or
distillation. See Supporting Information for further details.
a Yields are of material isolated by silica gel chromatography. Ratios
of 6:7 were determined by 19F NMR analyses of crude reaction mixtures.
DCyPM = 1,1-bis(dicyclohexylphosphino)methane, DCyPE = 1,1-
bis(dicyclohexylphosphino)ethane. See Supporting Information for li-
gand definitions and experimental details. b t-BuPPh2 (15 mol %).
Our study required a method for the synthesis of 1-aryl-
1-trifluoromethylallenes. Although syntheses involving
propargyl substitution using CF3 nucleophiles are
reported,10 these methods do not permit formation of
1-aryl-1-trifluoromethylallenes. Syntheses involving intro-
duction of the CF3 group at an early stage have been
reported, but do not employ readily accessible starting
materials and are not step-economic.11 Classical strategies
for allene synthesis, such as the DoeringÀLaFlamme
method,12 were unsuccessful. Hence, an effective protocol
for the synthesis of 1-aryl-1-trifluoromethylallenes was
developed (Scheme 1). CoreyÀFuchs olefination of the
aryl trifluoromethyl ketones 1aÀ1f13 delivers the corre-
sponding methylene dibromides 2aÀ2f. Lithiation14 of the
resulting methylene dibromides 2aÀd followed by treat-
ment with paraformaldehyde and quenching with metha-
nesulfonyl chloride delivers the allylic sulfonates 4aÀ4d,
which appear as single geometrical isomers. The allylic
sulfonates 4aÀ4d were converted to the corresponding
allylic bromides in situ and then exposed to zinc dust15 to
form allenes 5aÀ5d in good isolated yields. The vinyl-
lithium species derived from methylene dibromides2e,f did
not react efficiently with paraformaldehyde, but could be
methylated in good yield to form adducts 3e,f as single
geometrical isomers. Allylic bromination, which occurs
(6) (a) Ngai, M.-Y.; Skucas, E.; Krische, M. J. Org. Lett. 2008, 10,
2705. (b) Smejkal, T.; Han, H.; Breit, B.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 10366. (c) Bausch, C. C.; Patman, R. L.; Breit, B.;
€
Krische, M. J. Angew. Chem., Int. Ed. 2011, 50, 5687. (d) Kopfer, A.;
Sam, B.; Breit, B.; Krische, M. J. Chem. Sci. 2013, 4, 1876.
(7) Organofluorine compounds represent over 20% of approved
pharmaceutical agents and 30À40% of commercially available agro-
chemicals: (a) Thayer, A. M. Chem. Eng. News 2006, 84, 15. (b) Mueller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Thayer, A. M.
Chem. Eng. News 2007, 85, 11. (d) 80% of the small molecule drugs
entering the market are estimated to contain one or more chiral centers:
Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol.
Chem. 2006, 4, 2337. (e) Farina, V.; Reeves, J. T.; Senanayake, C. H.;
Song, J. J. Chem. Rev. 2006, 106, 2734.
(8) CF3-bearing all-carbon quaternary stereocenters are uncommon:
(a) Fuchigami, T.; Nakagawa, Y. J. Org. Chem. 1987, 52, 5276. (b)
Gosmini, C.; Rollin, Y.; Perichon, J.; Wakselman, C.; Tordeux, M.;
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Kitazume, T. Chem. Commun. 1997, 1497. (d) Sato, K.; Takiguchi, Y.;
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I.; Ando, A. Chem. Pharm. Bull. 2007, 55, 1593. (e) Kimura, M.;
Yamazaki, T.; Kitazume, T.; Kubota, T. Org. Lett. 2004, 6, 4651.
(9) For preparation of organofluorine substructures via iridium
catalyzed CÀC bond forming transfer hydrogenation, see: (a) Gao,
X.; Zhang, Y. J.; Krische, M. J. Angew. Chem., Int. Ed. 2011, 50, 4173.
(b) Hassan, A.; Montgomery, T. P.; Krische, M. J. Chem. Commun.
2012, 4692.
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R.; Laubender, M.; Windmuller, B.; Steinet, P.; Gevert, O.; Wolf, J.
J. Am. Chem. Soc. 2002, 124, 6966. (c) Han, H. Y.; Kim, M. S.; Son, J. B.;
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Commun. 1991, 566. (b) Morken, P. A.; Bachand, P. C.; Swenson, D. C.;
Burton, D. J. J. Am. Chem. Soc. 1993, 115, 5430. (c) Uno, H.; Nibu, N.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Proposed Mechanism for Ruthenium Catalyzed
Reductive Coupling of CF3-Substituted Allenes 5aÀ5f to
Paraformaldehyde
Figure 1. Ruthenium catalyzed reductive coupling of allenes
5aÀ5f to paraformaldehyde to form CF3-substituted neopentyl
alcohols 6aÀ6f. Yields are of material isolated by silica gel
chromatography. Ratios of 6:7 were determined by 19F NMR
analyses of crude reaction mixtures. See Supporting Informa-
tion for further details.
p-toluenesulfonate and reacted with sodium cyanide in
DMSO solvent. Despite the notoriously low rates typically
observed in SN2 reactions of neopentyl electrophiles, nitrile
8a was formed in moderate yield (eq 1). Jones oxidation of
neopentyl alcohol 6a followed by Fischer esterification
provides the methyl ester 9a (eq 2).
with scrambling of olefin geometry, followed by treatment
with zinc dust provided allenes 5e,f.
Having defined serviceable routes to allenes 5aÀ5f, the
reductive coupling of allene 5a to paraformaldehyde was
explored. Exposure to conditions previously developed for
ruthenium catalyzed reductive coupling of 1,1-disubstituted
allenes to paraformaldehyde provided the desired reductive
coupling product 6a in poor yield (Table 1, entry 1).6a
Various ruthenium(II) complexes were evaluated (Table 1,
entries 2À4). The commercially available complex RuHCl-
(CO)(PPh3)3 provided a promising 37% yield of 6a
(Table 1, entry 3).16 Upon addition of DPPF, the isolated
yield of 6a increased to 68%; however, small quantities of
over-reduction product 7a were apparent (Table 1, entry 6).
In fact, the extent of over-reduction and conversion exhib-
ited a dramatic dependence on ligand (Table 1, entries
6À15). Eventually, it was found that the combination of
RuHCl(CO)(PPh3)3 and DPPM provided a 78% isolated
yield of 6a with nearly complete suppression of over-reduction
(Table 1, entry 10).
Under these conditions, 1-aryl-1-trifluoromethylallenes
5aÀ5f were reductively coupled to paraformaldehyde to
provide the CF3-substituted primary neopentyl alcohols
6aÀ6f in moderate to good isolated yields (Figure 1). In all
cases, complete levels of branched regioselectivity were
observed. Only in the coupling of allene 5e was any
significant quantity of over-reduction product 7e ob-
served. To illustrate the utility of the reaction products,
neopentyl alcohol 6a was converted to the corresponding
A plausible catalytic mechanism for the ruthenium
catalyzed reductive coupling of CF3-substituted allenes
5aÀ5f to paraformaldehyde has been proposed (Scheme 2).
Ruthenium hydride I hydrometallates the allene to provide
the allylruthenium haptomers IIa and IIb.17,18 Addition to
formaldehyde from the primary σ-allylruthenium haptomer
IIa provides the ruthenium alkoxide III. At this stage, iso-
propanol can protonolytically cleave the ruthenium alkoxide
(17) For leading references on the stoichiometric reaction of HXRu-
(CO)(PR3)3 (X = Cl, Br) with allenes or dienes to furnish π-allylruthe-
nium complexes, see: (a) Hiraki, K.; Ochi, N.; Sasada, Y.; Hayashida,
H.; Fuchita, Y.; Yamanaka, S. J. Chem. Soc., Dalton Trans. 1985, 873.
(b) Hill, A. F.; Ho, C. T.; Wilton-Ely, D. E. T. Chem. Commun. 1997,
2207. (c) Xue, P.; Bi, S.; Sung, H. H. Y.; Williams, I. D.; Lin, Z.; Jia, G.
Organometallics 2004, 23, 4735.
(18) For studies involving π-allylruthenium complexes of the type
Ru(η3-allyl)(X)(CO)(PR3)2, see: (a) Barnard, C. F. J.; Daniels, B. J. A.;
Holland, P. R.; Mawby, R. J. J. Chem. Soc., Dalton Trans. 1980, 2418.
(b) Hiraki, K.; Matsunaga, T.; Kawano, H. Organometallics 1994, 13,
1878. (c) Sasabe, H.; Nakanishi, S.; Takata, T. Inorg. Chem. Commun.
2002, 5, 177. (d) Cadierno, V.; Crochet, P.; Diez, J.; Garcia-Garrido,
S. E.; Gimeno, J. Organometallics 2003, 22, 5226.
(16) The complex RuHCl(CO)(PPh3)3 served as an effective preca-
talyst in the redox neutral coupling of 1,1-disubstituted allenes and
primary alcohols: Zbieg, J. R.; McInturff, E. L.; Leung, J. C.; Krische,
M. J. J. Am. Chem. Soc. 2011, 133, 1141.
Org. Lett., Vol. XX, No. XX, XXXX
C

III to liberate the product 6 and generate ruthenium isoprop-
oxide IV, which upon β-hydride elimination regenerates
ruthenium hydride I. Alternatively, ruthenium alkoxide III
can undergo formaldehyde addition to form ruthenium alk-
oxide V, which upon β-hydride elimination provides the ester
6-formate. In all prior ruthenium catalyzed reductive cou-
plings of paraformaldehyde developed in our laboratory,6
including reactions of allenes,6a formate esters are generated
to a significant extent and are cleaved upon isolation of the
product.
In summary, we report a ruthenium catalyzed reductive
coupling of allenes 5aÀ5f to paraformaldehyde to form
CF3-substituted neopentyl alcohols 6aÀ6f under the con-
ditions of isopropanol mediated transfer hydrogenation.
Thisisone ofveryfew methodsavailableforthe generation
of all-carbon quaternary stereocenters bearing CF3
groups.8 Beyond access to these elusive functional group
arrays, the present study also describes novel synthetic
routes to 1-aryl-1-trifluoromethylallenes 5aÀ5f, which
may find use in other methodological endeavors. Future
studies will focus on the development of related CÀC bond
forming transfer hydrogenations, including asymmetric
variants of the transformations reported herein.
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1 GM069445), and the Center for Green Chemistry
and Catalysis for partial support of this research. Alison R.
Brown and Ke Qu are acknowledged for skillful technical
assistance.
Supporting Information Available. Spectral data for all
new compounds (1H NMR, 13C NMR, 19F NMR, IR,
MS). This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX