All-carbon quaternary centers via ruthenium-catalyzed hydroxymethylation of 2-substituted butadienes mediated by formaldehyde: Beyond hydroformylation

Article abstract of DOI:10.1021/ja904124b

(Chemical Equation Presented) Ruthenium-catalyzed transfer hydrogenation of 2-substituted dienes 1a-i in the presence of paraformaldehyde results in reductive coupling at the 2-position to furnish the hydroxymethylation products 3a-i, which embody all-car

Full text of DOI:10.1021/ja904124b

Published on Web 07/13/2009
All-Carbon Quaternary Centers via Ruthenium-Catalyzed Hydroxymethylation of
2-Substituted Butadienes Mediated by Formaldehyde: Beyond Hydroformylation
Tomas Smejkal,†,‡,§ Hoon Han,§ Bernhard Breit,*,†,‡ and Michael J. Krische*,‡,§
Institut fu¨r Organische Chemie und Biochemie and Freiburg Institute for AdVanced Studies (FRIAS),
Albert-Ludwigs-UniVersita¨t Freiburg, 79104 Freiburg, Germany, and Department of Chemistry and Biochemistry,
UniVersity of Texas at Austin, Austin, Texas 78712
Received May 21, 2009; E-mail: bernhard.breit@chemie.uni-freiburg.de; mkrische@mail.utexas.edu
Table 1. Ruthenium-Catalyzed Reductive Coupling of 2-Substituted
Dienes 1a-i to Paraformaldehyde via Transfer Hydrogenationa
Hydroformylation is the largest-volume application of homoge-
neous metal catalysis and the prototypical C-C bond-forming hydro-
genation.1 Whereas alkene hydroformylation is well-developed, the
hydroformylation of conjugated dienes has proven especially chal-
lenging.2 As part of a broad program aimed at the development of
hydrogen-mediated C-C bond formations beyond hydroformylation,3
one of the present authors reported ruthenium-catalyzed reductive
couplings of carbonyl compounds to various unsaturates,4-6 including
dienes,4a,b allenes,4c,d alkynes,4e,f and enynes.4g In lieu of efficient
protocols for diene hydroformylation, the ruthenium-catalyzed reductive
coupling of dienes to paraformaldehyde, an abundant C1 feedstock,
was investigated. Here, we report that ruthenium-catalyzed transfer
hydrogenation of 2-substituted dienes in the presence of paraformal-
dehyde delivers products of reductive C-C coupling in good yield.
Remarkably, and in contrast to prior work on diene-carbonyl reductive
coupling,4-8 conditions that promote interconversion of π-allyl A to
the isomeric π-allyl B were identified,9 enabling C-C coupling at the
2-position of the diene to furnish products incorporating all-carbon
quaternary centers.
a In each case, the cited yield is of isolated material and represents
the average of two runs. See the Supporting Information for detailed
experimental procedures. b 2-Propanol/Me2CO (1 M, 9:1) was used as
the solvent. c 2-Propanol (1 M) was used as the solvent. d The reaction
time was extended to 40 h.
It was hypothesized that the relative energies of the competing
transition structures for carbonyl addition dictate the distribution
of products 2 and 3. If one assumes intervention of a chairlike
transition structure, the path to isomers 2 mandates pseudoaxial
orientation of the diene 2-substituent (Scheme 1). Hence, a larger
2-substituent should disfavor formation of isomers 2. Indeed,
exposure of the cyclohexyl-substituted diene 1b to the aforemen-
tioned reaction conditions resulted in formation of the primary
neopentyl alcohol 3b as a single regioisomer (Table 1). Branching
directly adjacent to the 2-position is not required, as illustrated by
the formation of adducts 3c and 3e. However, sterically demanding
groups are required at O and N, respectively, to maintain complete
levels of regioselectivity. To probe the potential for substrate-
induced diastereoselectivity, dienes 1d and 1f, which possess a
preexisting stereogenic center, were subjected to the standard
reaction conditions. However, the resulting neopentyl alcohols were
formed as equimolar mixtures of diastereomers. Finally, as dem-
onstrated by the formation of adducts 3g-i,11 2-aryl-1,3-butadienes
are subject to highly regioselective hydroxymethylation.
Initial studies focused on the reductive coupling of myrcene 1a
to paraformaldehyde. Upon an assay of our previously disclosed
conditions,4a,b the catalyst prepared in situ from RuHCl(CO)(PPh3)3
and rac-BINAP was most effective, providing an 18% isolated yield
of the C-C coupling product. Surprisingly, this product appeared
as an equimolar mixture of the anticipated adduct 2a and its
regioisomer 3a, wherein coupling occurs at the substituted position
of the diene to furnish the all-carbon quaternary center. It was
postulated that product 3a forms through isomerization of π-allyl
isomer A to π-allyl isomer B by way of reversible ꢀ-hydride elim-
ination-diene hydrometalation. On the basis of this hypothesis,
ruthenium catalysts that embody greater cationic character were
assayed, as coordinative unsaturation should promote ꢀ-hydride
elimination, potentially accelerating isomerization. Indeed, upon
an assay of counterions, it was found that RuH(O2CC7F15)(CO)-
(dppb)(PPh3), prepared in situ from RuH2(CO)(PPh3)3 and HO2-
CC7F15,10 provides a 76% isolated yield of C-C coupling product
as a 1:4 mixture of isomers 2a and 3a, respectively, in the presence
of dppb.
To gain further mechanistic insight, isotopic labeling studies were
undertaken. Diene 1g was subjected to three separate experiments
employing deuterio-paraformaldehyde, 2-propanol-d8, or both deu-
terio-paraformaldehyde and 2-propanol-d8 under otherwise standard
† Institut fu¨r Organische Chemie und Biochemie.
‡ Freiburg Institute for Advanced Studies (FRIAS).
§ University of Texas at Austin.
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10366 J. AM. CHEM. SOC. 2009, 131, 10366–10367
10.1021/ja904124b CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Isotopic Labeling Studies Exclude Hydroformylation
in reductive coupling at the 2-position to furnish products of
hydroxymethylation that contain all-carbon quaternary centers. This
process represents an alternative to 1,3-diene hydroformylation, for
which efficient regioselective catalytic systems remain undeveloped.
Acknowledgment. Acknowledgment is made to the Robert A.
Welch Foundation, NIH-NIGMS (RO1-GM069445), and the
FRIAS for partial support of this research.
Pathways and Corroborate Reversible Diene Hydrometallationa
(CD2O)n + i-PrOH
(CH2O)n + i-PrOH-d8
(CD2O)n + i-PrOH-d8
Ha (5% 2H)
Ha (51.5% 2H)
Ha (17% 2H)
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Hb (100% 2H)
Hc (16.5% 2H)
Hd (12% 2H)
He (14% 2H)
Hb (0% 2H)
Hb(100% 2H)
Hc (76.5% 2H)
Hd (58.5% 2H)
He (57.5% 2H)
Hc (46% 2H)
Hd (51% 2H)
He (50% 2H)
References
(1) For selected reviews on hydroformylation, see: (a) Weissermel, K.; Arpe,
H.-J. Industrial Organic Chemistry; Wiley-VCH, Weinheim, Germany,
2003; pp 127-144. (b) Rhodium Catalyzed Hydroformylation; van Leeu-
wen, P. W. N. M., Claver, C., Eds.; Kluwer: Dordrecht, The Netherlands,
2000. (c) Breit, B.; Seiche, W. Synthesis 2001, 1.
a The extent of 2H incorporation was determined using 1H and 2H
NMR spectroscopy. The indicated values represent averages of two runs.
Scheme 1. Plausible Catalytic Mechanism Accounting for the
Results of Isotopic Labeling
(2) Hydroformylation of conjugated dienes typically occurs in low yield to
provide complex mixtures. 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 Leeuwen, P. W. N. M.; Roobeek, C. F. J. Mol. Catal. 1985, 31, 345. (f)
Chalchat, J. C.; Garry, R. P.; Lecomte, E.; Michet, A. FlaVour Fragrance J.
1991, 6, 178. (g) Bertozzi, S.; Campigli, N.; Vitulli, G.; Lazzaroni, R.; Salvadori,
P. J. Organomet. Chem. 1995, 487, 41. (h) Horiuchi, T.; Ohta, T.; Nozaki, K.;
Takaya, H. Chem. Commun. 1996, 155. (i) Horiuchi, T.; Ohta, T.; Shirakawa,
E.; Nozaki, K.; Takaya, H. Tetrahedron 1997, 53, 7795. (j) Barros, H. J. V.;
Hanson, B. E.; dos Santos, E. N.; Gusevskaya, E. V. Appl. Catal., A 2004, 278,
57. (k) Barros, H. J. V.; da Silva, J. G.; Guimara˜es, C. C.; dos Santos, E. N.;
Gusevskaya, E. V. Organometallics 2008, 27, 4523.
(3) For selected reviews of C-C bond-forming hydrogenation and transfer
hydrogenation, see: (a) Ngai, M.-Y.; Kong, J. R.; Krische, M. J. J. Org.
Chem. 2007, 72, 1063. (b) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische,
M. J. Acc. Chem. Res. 2007, 40, 1394. (c) Bower, J. F.; Kim, I. S.; Patman,
R. L.; Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34.
(4) For Ru-catalyzed C-C bond-forming transfer hydrogenation, see: Dienes: (a)
Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130,
6338. (b) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 14120. Allenes: (c) Ngai, M.-Y.; Skucas, E.; Krische, M. J.
Org. Lett. 2008, 10, 2705. (d) Skucas, E.; Zbieg, J. R.; Krische, M. J. J. Am.
Chem. Soc. 2009, 131, 5054. Alkynes: (e) Patman, R. L.; Chaulagain, M. R.;
Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066. (f)
Williams, V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J. Tetrahedron
2009, 65, 5024. Enynes: (g) Patman, R. L.; Williams, V. M.; Bower, J. F.;
Krische, M. J. Angew. Chem., Int. Ed. 2008, 47, 5220.
(5) For related catalytic C-C couplings that occur by way of nucleophilic Ru
π-allyls, see: (a) Tsuji, Y.; Mukai, T.; Kondo, T.; Watanabe, Y. J.
Organomet. Chem. 1989, 369, C51. (b) Kondo, T.; Ono, H.; Satake, N.;
Mitsudo, T.-a.; Watanabe, Y. Organometallics 1995, 14, 1945. (c) Kondo,
T.; Hiraishi, N.; Morisaki, Y.; Wada, K.; Watanabe, Y.; Mitsudo, T.-a.
Organometallics 1998, 17, 2131. (d) Yu, C.-M.; Lee, S.; Hong, Y.-T.; Yoon,
S.-K. Tetrahedron Lett. 2004, 45, 6557. (e) Omura, S.; Fukuyama, T.;
Horiguchi, J.; Murakami, Y.; Ryu, I. J. Am. Chem. Soc. 2008, 130, 14094.
(6) For selected reviews of Ru-catalyzed C-C coupling, see: (a) Trost, B. M.;
Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101, 2067. (b) Kondo, T.;
Mitsudo, T.-a. Curr. Org. Chem. 2002, 6, 1163. (c) De´rien, S.; Monnier,
F.; Dixneuf, P. H. Top. Organomet. Chem. 2004, 11, 1.
(7) For catalytic intermolecular diene-aldehyde reductive coupling, see: (a)
Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998,
120, 4033. (b) Takimoto, M.; Hiraga, Y.; Sato, Y.; Mori, M. Tetrahedron
Lett. 1998, 39, 4543. (c) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata,
K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew. Chem., Int. Ed. 1999,
38, 397. (d) Kimura, M.; Shibata, K.; Koudahashi, Y.; Tamaru, Y.
Tetrahedron Lett. 2000, 41, 6789. (e) Kimura, M.; Ezoe, A.; Tanaka, S.;
Tamaru, Y. Angew. Chem., Int. Ed. 2001, 40, 3600. (f) Loh, T.-P.; Song,
H.-Y.; Zhou, Y. Org. Lett. 2002, 4, 2715. (g) Sato, Y.; Sawaki, R.; Saito,
N.; Mori, M. J. Org. Chem. 2002, 67, 656. (h) Jang, H.-Y.; Huddleston,
R. R.; Krische, M. J. Angew. Chem., Int. Ed. 2003, 42, 4074. (i) Bareille,
L.; Le Gendre, P.; Mo¨ıse, C. Chem. Commun. 2005, 775. (j) Kimura, M.;
Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y. J. Am. Chem. Soc. 2006, 128,
8559. (k) Yang, Y.; Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, L.-X.;
Zhou, Q.-L. J. Am. Chem. Soc. 2007, 129, 2248. (l) Sato, Y.; Hinata, Y.;
Seki, R.; Oonishi, Y.; Saito, N. Org. Lett. 2007, 9, 5597.
conditions (Table 2). The observed patterns of deuterium incorpora-
tion exclude pathways involving ruthenium-catalyzed hydroformy-
lation,12 potentially enabled through decomposition of paraform-
aldehyde to form syngas (CO/H2). Rather, these data are consistent
with a scenario involving diene hydrometalation-ꢀ-hydride elimi-
nation at different positions of the diene by way of intermediates
A-D. Formaldehyde addition from the primary σ-allyl haptomer
derived from B through a chairlike transition structure is postulated
to provide isomers 3 (Scheme 1). As previously discussed, strain
associated with the pseudoaxial orientation of large diene 2-sub-
stituents appears to disfavor formation of isomers 2. In contrast,
the transition structure en route to isomers 3 involves pseudoequa-
torial orientation of the diene 2-substituents and projection of these
groups into open volumes of space.
Formaldehyde hemiacetals mediate reductive coupling in com-
1
petition with 2-propanol. H NMR analyses of the crude reaction
mixtures reveal both acetone and isopropyl formate. Additionally,
in the absence of 2-propanol but under otherwise standard condi-
tions, diene 1g is converted to formate esters 2g-formate and
3g-formate in 42% isolated yield as a 1:4 ratio of regioisomers,
respectively. The difference in crystallinity and, hence, solubility
between paraformaldehyde and deuterio-paraformaldehyde may
account for the observed drop in deuterium incorporation for Ha
upon use of deuterio-paraformaldehyde and 2-propanol-d8 instead
of paraformaldehyde and 2-propanol-d8.
(8) For a recent review encompassing Ni-catalyzed diene-aldehyde reductive
coupling, see: Kimuara, M.; Tamaru, Y. Top. Curr. Chem. 2007, 279, 173.
(9) For isomerization of Ru π-allyls, see ref 5e and: Xue, P.; Bi, S.; Sung,
H. H. Y.; Williams, I. D.; Lin, Z.; Jia, G. Organometallics 2004, 23, 4735.
(10) Dobson, A.; Robinson, S. R.; Uttley, M. F. J. Chem. Soc., Dalton Trans.
1974, 370.
(11) Optically enriched 3g was previously prepared in 10 steps via enzymatic
resolution (see: Fadel, A.; Vandromme, L. Tetrahedron: Asymmetry 1999,
10, 1153. ). With the use of (R)-CatASium T2 as the ligand instead of
dppb, optically enriched 3g (57% ee) is accessible in only two steps.
(12) For a review of Ru-catalyzed alkene hydroformylation, see: Kalck, P.; Peres,
Y.; Jenck, J. AdV. Organomet. Chem. 1991, 32, 121.
In summary, ruthenium-catalyzed transfer hydrogenation of
2-substituted dienes in the presence of paraformaldehyde results
JA904124B
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