Conversion of propargylic alcohols to β-oxo esters catalyzed by novel ruthenium-phosphoramidite complexes

Article abstract of DOI:10.1002/adsc.200800355

A series of half-sandwich phosphoramidite complexes of ruthenium were synthesized and employed as catalysts in the atom-economical formation of β-oxo esters from carboxylic acids and propargylic alcohols. Reaction of the phosphoramidites (R)-BINOL-PNR2 (R=Me, 1a; i-Pr, 1b; benzyl, 1c) and (rac)-6,6′-dibromo-BINOL-PNMe₂ (1d) with the dimeric p-cymene-ruthenium dichloride complex, [RuCl₂(p-cymene)]₂, gave the complexes [RuCl₂(p-cymene)(L)] (L=1a, 7a; 1b, 7b; 1c, 7c; 1d, 7d) in 96-66% yield. Accordingly, reaction of (R)-BINOL(8H)-PNMe2 (2a) and (R)-BINOL(8H)-PN-(benzyl)₂ (2b) with [RuCl₂(p-cymene)] ₂ afforded the complexes [RuCl₂(p-cymene)(L)] (L=2a, 8a; 2b, 8b) in 82% and 86% yield. In a similar reaction, treatment of (R)-BIPHEN-PNMe₂ (9) with [RuCl₂(p-cymene)] ₂ gave the complex [RuCl₂(p-cymene)(9)] (11) in 60% yield. Finally, phosphoramidite 1b reacted with [RuCl₂(C₆Me ₆)]₂ to give [RuCl₂(C₆Me ₆)(1b)] (12) in 78% yield. All novel complexes are catalytically active in the formation of β-oxo esters from propargylic alcohols and carboxylic acids. Standard conditions involve cyclohexane solvent, propargylic alcohol (1.0 equiv.), carboxylic acid (1.0 equiv.), ruthenium catalyst (1.5 mol%), and 90°C for 5-18 h. Isolated yields of the β-oxo esters range from 87 to 16% and show broad substrate generality. The reaction proceeds without racemization if a chiral propargylic alcohol is employed. The method is practical as no additives are required and the exclusion of oxygen and moisture is not needed. Complex 7c turned out to be the most effective catalyst (5 h reaction time), showing that the ligand structure has a profound impact on the catalytic performance. The crystal structure of 7a was determined, confirming an octahedral coordination geometry about the ruthenium center.

Full text of DOI:10.1002/adsc.200800355

FULL PAPERS
DOI: 10.1002/adsc.200800355
Conversion of Propargylic Alcohols to b-Oxo Esters Catalyzed by
Novel Ruthenium-Phosphoramidite Complexes
Stephen Costin,a Nigam P. Rath,a and Eike B. Bauera,*
a
University of Missouri – St. Louis, Department of Chemistry and Biochemistry, One University Boulevard, St. Louis, MO
63121, USA
Fax : (+1)-314-516-5342; e-mail: bauere@umsl.edu
Received: June 7, 2008; Published online: September 24, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800355.
Abstract: A series of half-sandwich phosphoramidite propargylic alcohols and carboxylic acids. Standard
complexes of ruthenium were synthesized and em- conditions involve cyclohexane solvent, propargylic
ployed as catalysts in the atom-economical formation alcohol (1.0 equiv.), carboxylic acid (1.0 equiv.),
of b-oxo esters from carboxylic acids and propargylic ruthenium catalyst (1.5 mol%), and 908C for 5–18 h.
alcohols. Reaction of the phosphoramidites (R)- Isolated yields of the b-oxo esters range from 87 to
BINOL-PNR2 (R=Me, 1a; i-Pr, 1b; benzyl, 1c) and 16% and show broad substrate generality. The reac-
(rac)-6,6’-dibromo-BINOL-PNMe2 (1d) with the di- tion proceeds without racemization if a chiral prop-
meric p-cymene-ruthenium dichloride complex, argylic alcohol is employed. The method is practical
[RuCl
N
N
cymene)(L)] (L=1a, 7a; 1b, 7b; 1c, 7c; 1d, 7d) in oxygen and moisture is not needed. Complex 7c
96–66% yield. Accordingly, reaction of (R)- turned out to be the most effective catalyst (5 h reac-
BINOL(8H)-PNMe2 (2a) and (R)-BINOL(8H)-PN- tion time), showing that the ligand structure has a
A
N
AHCTREUNG
AHCTREUNG
AHCTREUNG
A
ACHTREUNG
(12) in 78% yield. All novel complexes are catalyti- dites; propargylic alcohols; ruthenium; X-ray struc-
cally active in the formation of b-oxo esters from ture determination
Introduction
ACHTREUNG
Phosphoramidites (Figure 1) have recently attracted
considerable interest as ligands in various transition
metal-catalyzed organic reactions. Phosphoramidites
are an attractive ligand class because they are rela-
tively easy to synthesize and are air-stable.[1] They
allow for steric and electronic fine tuning of their
metal complexes because their “architecture” can be
modified at several sites through choice of diol as
well as substituents on the diol backbone and on the
nitrogen.[2] Typically phosphoramidites are utilized in
situ in combination with a metal complex precursor to
yield efficient catalyst systems for such conversions as
enantioselective conjugate enone addition reac- Figure 1. Phosphoramidite ligands.
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Conversion of Propargylic Alcohols to b-Oxo Esters
FULL PAPERS
Alder[9] and Heck reactions.[10] The nature of the cata- describe the influence of different phosphoramidite li-
lytically active species for these in situ catalyst sys- gands on the reactivity of the metal complexes as well
tems is not always known.[11]
as experiments to better understand the mechanism
Phosphoramidites derived from BINOL(1,1 ’-bi- of the reaction.
naphthyl-2,2’-diol) are the most prevalent, but others
utilizing TADDOL, e.g., are known as well.[12] It has
been shown that changes at the phosphoramidite skel- Results
eton have a profound impact on yields and enantiose-
lectivities in catalytic applications of these ligands.[7]
Synthesis of Novel Half-Sandwich Ruthenium-
b-Oxo esters are an important class of com- Phosphoramidite Complexes
pounds.[13] Several synthetic methodologies to form
these esters are known,[14] e.g., from propargylic alco- First, a set of sterically and electronically tuned phos-
hols by a two-step hydration/esterification procedur- phoramidite ligands and their metal complexes were
e[14a,b] or by carboxylation of a-halo ketones.[14c,d] Ad- synthesized. The known chiral phosphoramidite li-
dition of carboxylic acids (4) to propargylic alcohols gands of the type 1a–d and 2a shown in Figure 1 were
(3) to form b-oxo esters (5) provides a quick, atom synthesized according to literature procedures.[1,7]
economical access to this class of compounds from Similarly, the new ligand 2b was synthesized as out-
simple starting materials in one step (Scheme 1). This lined in Eq. (1). Phosphorus trichloride (PCl3) was
heated in toluene with dibenzylamine [(PhCH2)2NH]
and triethylamine followed by the addition of com-
mercial (R)-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-binaphth-
yl-2,2’-diol (6) and the resulting slurry was stirred at
room temperature for 24 h. After work-up, the chiral
phosphoramidite 2b was obtained as a white powder
in 65% yield.
Scheme 1. b-Oxo ester formation from propargylic alcohols.
reaction does not proceed without a catalyst. To date,
only a few catalysts are known to promote this trans-
formation. Watanabe described a mixture of bis(h4-cy-
clooctadienyl)ruthenium,
trialkylphosphine
and
maleic anhydride,[15] that functions as an active cata-
lyst and Dixneuf showed that the half-sandwich com-
The dimeric ruthenium p-cymene chloro complex
2(p-cymene)]2 is known to give half-sandwich
(PPh3)]2 also complexes of the type [RuCl2(p-cymene)(L)] when
treated with monodentate phosphines[18a] or phosphor-
Steroids possessing a b-oxo ester motif in the C-17 amidites.[18b,c] Accordingly, the ligands 1a–d and 2a, b
position often show biological activity.[13a] b-Oxo were reacted with [RuCl
2(p-cymene)]2 under standard
plexes [RuCl
the dimeric complex [Ru
catalyze this reaction.[16b,c]
2(p-cymene)
(PR3)] (R=Ph, Me)[16a] and [RuCl
ACHTREUNG
(m-O2CH)(CO)2
G
ACHTREUNG
AHCTREUNG
esters are employed as intermediates in the formation conditions (CH2Cl2, room temperature, 16 h). As ex-
of a chiral acyloin,[13b] a key structural feature of emplified in Scheme 2 for the ligand class 1, chroma-
many natural products.[13c] It has been demonstrated tographic separation provided the novel chiral target
that they are also efficient photolabile protecting complexes [RuCl2(p-cymene)(L)] 7a–d (Scheme 2)
T
groups for carboxylic acids.[13d]
and 8a, b (Figure 2) as red powders in 96–66% yields.
The complexes 7 and 8 differ in the substituents at
It is known that a number of ruthenium complexes
activate propargylic alcohols catalytically.[17] Herein, the nitrogen of the phosphoramidite, but all are de-
we explore ruthenium phosphoramidite complexes as rived from BINOL(1,1 ’-binaphthyl-2,2’-diol) or
catalysts for b-oxo ester formation as shown in 5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-binaphthyl-2,2’-diol.
Scheme 1. For this purpose, we synthesized several We were interested to determine if phosphoramidites
novel, electronically and sterically tuned phosphora- derived from diols other than BINOLhave an impact
midite complexes of ruthenium, all of which are effi- on the catalytic properties of their respective metal
cient catalysts for the conversion of propargylic alco- complexes. We also sought some steric tuning closer
hols and carboxylic acids to b-oxo esters. Herein we to the ruthenium metal center. Substituents in the
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Stephen Costin et al.
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in 60% yield. Subsequently, ligand 10 was refluxed
with [RuCl2(p-cymene)]2 in ClCH2CH2Cl and com-
A
plex 11 was isolated by extraction with diethyl ether
in 61% yield as a purple solid.[19]
In order to investigate the influence of the arene
ligand at ruthenium, complex 12 was synthesized,
which bears the hexamethylbenzene ligand, C6Me6,
instead of the p-cymene ligand [Eq. (2)]. The
Scheme 2. Phosphoramidite complex synthesis.
known[20] dimer [RuCl2
(C6Me6)]2 was refluxed with
A
Figure 2. Phosphoramidite complexes.
phosphoramidite 1b in CH2Cl2 for 6 h and the C6Me6
complex 12 was isolated as an orange powder in 78%
yield, which showed ca. 95% spectroscopic purity.[19]
Complexes 7a–d, 8a, b, 11 and 12 were character-
ized by mass spectrometry, IR and NMR (1H, 13C, 31P)
3,3’-positions ortho to the oxygen substituents in
BINOLseemed to hold the greatest promise. When
coordinated to a metal, substituents in this position spectroscopy and microanalysis. The 31P NMR shifts
would point directly towards the metal center.
ranged between 141 and 143 ppm for 7b–d and 8a.
Thus, commercial (R)-5,5’,6,6’-tetramethyl-3,3’-di- Deviations from this range were detected for complex
tert-butyl-1,1’-biphenyl-2,2’-diol [“(R)-BIPHEN’’, 9] 7a (151.5 ppm), complex 8b (136.8 ppm), for the (R)-
was heated to 1008C for 12 h with hexamethylphos- BIPHEN complex 11 (125.6 ppm) and the C6Me6
1
phorus triamide (HMPT) according to literature pro- complex 12 (158.3 ppm). The H and 13C NMR spec-
tocols (Scheme 3).[1a] After recrystallization, the new tra are in accordance with the proposed structures.
phosphoramidite 10 was obtained as a white powder For example, the coordination geometry of 7 and 8
creates four inequivalent aromatic CH groups for the
p-cymene ligand. Accordingly, these complexes exhib-
ited six aromatic signals in the 13C NMR and four aro-
matic signals in the 1H NMR spectra for the p-
cymene ligand. Similarly, the hydrogen atoms of the
two NCH2Ph groups in complex 7c and 8b are diaste-
reotopic, and as a consequence, four individual signals
1
were observed in the H NMR.
To unequivocally establish the structures of the new
phosphoramidite complexes, the crystal structure of
complex 7a was determined (Experimental Section
and Table S1 in the Supporting Information).
The molecular structure is depicted in Figure 3
along with key structural data, confirming the half-
sandwich configuration about ruthenium. Bond
lengths and angles are as expected, and similar to
those reported for closely related complexes.[18b] The
bond angles around ruthenium range from 84.08(3)8
À
À
for the P(1) Ru(1) Cl(1) angle to 94.30(11)8 for the
À
À
Cl(2) Ru(1) C(2) angle. Thus, the coordination ge-
ometry of the complex is best described as a slightly
distorted octahedron. The bulky phosphoramidite
Scheme 3. Synthesis of ruthenium BIPHEN phosphorami-
dite complex 11.
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Conversion of Propargylic Alcohols to b-Oxo Esters
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Both acetic and benzoic acid can be used. As outlined
in Table 2, cyclic tertiary propargylic alcohols were
converted to the corresponding cyclic b-oxo esters
and 2-bromobenzoic acid could be employed as well
(Table 1, entries 2, 5, 8, 13 and 15 and Table 2, en-
tries 2 and 5).
The yields showed only moderate substrate depend-
ence but did not exceed 57% for complex 7a under
the reaction conditions reported here. Conversions
with 7a reached 100%, but side products formed
during the reaction (vide infra). Next, electronically
or sterically modified ruthenium complexes were
tested to determine whether the catalytic activity
could be improved.
Screening of the metal complexes 7b, 7c, 8a, 8b, 11
and 12 revealed that all complexes are catalytically
active in the title reaction. Further investigations re-
vealed that the N-benzyl complex 7c catalyzed the
transformation at higher reaction rates than the N-
methyl complex 7a, as it took only 5 h at 908C for
complete conversion. Complex 7a required 18 h to
completely convert the starting materials. The isolated
yields from 7c were higher in all cases than those
from 7a, as seen in Table 1 and Table 2. For complex
7a, the yields range from 16 to 57%, whereas they
range from 24 to 87% for complex 7c. GC analyses
showed, in general, fewer side products than the cor-
responding reactions with catalyst 7a. Thus, exchange
of a methyl group on nitrogen in the phosphoramidite
Figure 3. Molecular structure of complex 7a. Key bond
lengths (Š) and angles (8): Ru(1) P(1)=2.2778(10); P(1)
À
À
À
À
N(1)=1.642(3);
Ru(1) Cl(1)=2.4136(9);Ru(1) Cl(2)=
À
À
À
À
2.3901(9);
P(1) Ru(1) Cl(1)=84.08(3);
P(1) Ru(1)
À
À
À
Cl(2)
Cl(2)=85.15(3);
Cl(2) Ru(1) Cl(1)=88.85(3);
À
À
À
Ru(1) (C2)=94.30(11);
O(1) P(1) O(2)=100.86(13);
À
À
À
À
O(1) P(1) N(1)=110.36(14); O(2) P(1) N(1)=97.26(13).
ligand is directed opposite to the isopropyl substituent ligand in 7a for a benzyl group in 7c resulted in a
on p-cymene, presumably for steric reasons.
complex with much better catalytic performance.
In order to assess the relative activity of the com-
plexes 7, 8, 11 and 12, the complexes were utilized
under strictly comparable conditions for b-oxo ester
formation from benzoic acid 4a and 2-phenyl-3-butyn-
2-ol 3e (entry 12 in Table 1). Conversion and relative
Application of the Ruthenium-Phosphoramidite
Complexes in Catalysis
Since 7a is the most easily accessible complex, it was yields were determined by GC/MS after two and four
employed for initial catalytic studies and optimiza- hours reaction time and the results are summarized in
tions. After screening different substrates and sol- Table 3. For comparison, the known complex [RuCl2
vents, complex 7a was found to be catalytically active
U
G
cohols to give b-oxo esters (Scheme 1). The results of well.
the catalytic experiments are summarized in Table 1
It turns out that among the complexes 7, 8, 11 and
and Table 2 and characterization data (NMR, IR, 12, the N-benzyl complex 7c exhibited the highest ac-
MS) for the products are given in the Supporting In- tivity. Complete conversion after 4 h was observed for
formation. The best results were obtained when cyclo- this specific test reaction, and the product was detect-
hexane was used as solvent. Reactions conducted in ed in 97% GC yield. Isolated yields were somewhat
THF or ClCH2CH2Cl were incomplete or plagued by lower, presumably due to the presence of light or oli-
side products. Using 1.5 mol% of the catalyst and a gomeric by-products. The octahydro N-benzylphos-
1:1 mol ratio of the reactants, moderate to good iso- phoramidite complex 8b showed comparable activity.
lated yields were obtained after 18 h at 908C. The ex- Lower conversions and yields were observed with the
clusion of moisture or air was not necessary.
N-isopropyl complex 7b and the N-methyl complex
Tertiary aliphatic and aromatic propargylic alcohols 7a. When the p-cymene ligand was exchanged by
could be converted to the corresponding esters (en- C6Me6 (complex 12), the activity dropped as well.
tries 9–15, Table 1) as well as secondary aliphatic and Also, electron-withdrawing bromo substituents in the
aromatic alcohols (entries 3–8) and the primary prop- BINOLbackbone (complex 7d) lowered the catalytic
argylic alcohol prop-2-yn-1-ol (3a, entries 1 and 2). activity. Obviously the N-benzyl substituent makes a
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Table 1. b-Oxo ester formation.
[a]
[b]
[c]
Isolated yields after column chromatography. GC/MS of the crude product showed complete
consumption of the propargylic alcohol and one major peak for the product.
Conditions: propargylic alcohol (0.7 mmol), carboxylic acid (0.7 mmol), catalyst 7a
(0.012 mmol) 18 h in cyclohexane (3 mL) at 908C.
Conditions: propargylic alcohol (0.7 mmol), carboxylic acid (0.7 mmol) and the catalyst 7c
(0.006–0.012 mmol), 5 h in cyclohexane (3 mL) at 908C.
Table 2. Cyclic b-oxo ester formation.
[a]
Isolated yields after column chromatography.
Conditions identical to those in Table 1.
Conditions identical to those in Table 1.
[b]
[c]
big difference, because the two phosphoramidite com- Reactivity Studies
plexes 7c and 8b bearing this substituent showed the
highest activity among the phosphoramidite com- Analysis of the crude reaction mixtures of the catalyt-
plexes under investigation. The complex [RuCl
cymene)(PPh3)] showed performance comparable to NMR) revealed that an unsaturated hydrocarbon con-
N-benzyl complex 7c. stituted the major side product for catalyst 7a. A
A
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Conversion of Propargylic Alcohols to b-Oxo Esters
Table 3. Comparison of different catalysts.
FULL PAPERS
For the catalytic experiments in Table 1 and
Table 2, racemic (or achiral) propargylic alcohols
were employed. As assessed by H NMR experiments
1
with a chiral shift reagent for some of the reactions in
Table 1, virtually no enantiomeric excesses were ob-
tained with the chiral complex 7a as catalyst. In order
to obtain additional information concerning the ste-
reochemistry of the reaction, the commercial chiral
propargylic alcohol (R)-17 (96% ee) was subjected to
b-oxo ester formation with catalyst 7c, as shown in
Eq. (3). The reaction proceeded without racemiza-
tion. The enantiomeric excess for the product 18 was
96% as determined by chiral GC and the traces of the
experiments are displayed in the Supporting Informa-
tion.
[a]
Conditions: 0.7 mmol propargylic alcohohl 3e, 0.7 mmol
benzoic acid 4a, 0.012 mmol catalyst in cyclohexane
(3 mL) at 908C.
Determined by the peak intensity of the starting material
[b]
vs. the total peak area in the GC/MS.
Determined by the peak intensity of the product vs. the
[c]
To gain further insight into relative reactivities and
the course of the reaction, product formation for the
reaction in entry 12 in Table 1 was followed over time
by GC for the most active phosphoramidite complex
7c. An induction period of about 30 min was ob-
served, as seen in Figure 4. The same experiment was
total peak area in the GC/MS.
In toluene.
In a 6:1 cyclohexane/p-cymene mixture.
[d]
[e]
ketone was also detected in some cases. Other side performed with [RuCl
N
N
products typically were detected only in trace quanti- plex gave an almost identical trace (see Figure 4),
ties. As exemplified by propargylic alcohol 3d in demonstrating that its activity is close to that of the
Scheme 4, the major side product arises from the N-benzyl complex 7c. The C6Me6 complex 12 exhibit-
ed a longer induction period and a slower reaction
rate for the same reaction under identical conditions.
The longest induction period (about 80 min) and
slowest reaction rate was observed with the complex
7a.
To determine if arene loss from the metal complex
is one of the steps in the mechanism of the reaction,
toluene and a 6:1 mixture of cyclohexane/p-cymene
were employed as solvent in the test reaction sum-
marized in Table 3. The reaction is only slightly
slower when coordinating aromatic compounds are
present, suggesting that arene loss is not a part of the
reaction.
Scheme 4. Side product formation.
cleavage of the triple bond, which presumably occurs
via an allenylidene intermediate 16 (Scheme 4). This Discussion
reaction pattern has previously been observed.[21] Ac-
cordingly, when propargylic alcohol 3d was heated The preceding data show for the first time that ruthe-
with a catalytic amount of 7a in cyclohexane in the nium phosphoramidite complexes are efficient cata-
absence of a carboxylic acid, at about 75% conversion lysts for b-oxo ester formation from propargylic alco-
the cleavage products 14 and 15 were detected by hols and carboxylic acids. The ruthenium complexes
GC/MS in approximately a 1:1 ratio (Scheme 4).
7, 8, 11 and 12 described herein are easily accessed in
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Stephen Costin et al.
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Figure 4. Product formation of the reaction in entry 12 in Table 1 followed over time by GC for different catalysts.
good yields from phosphoramidite ligands, which are 60% yields (808C, 10–24 h).[16b] The same dimeric
in turn synthesized in one or two steps from commer- ruthenium complex was applied in the conversion of
cially available starting materials according to litera- sterically hindered tertiary propargylic alcohols of ste-
ture procedures. The ligand has a profound impact on roids and bulky carboxylic acids to obtain the corre-
the catalytic activity. The N-benzyl complex 7c sponding b-oxo esters in 94–56% yields.[16c] In these
showed the highest activity, with isolated yields of b- cases, three equivalents of acetic acid or formic acid
oxo esters ranging from 24 to 87%. The catalytic per- were required, and reaction times were 15–16 h at
formance of 7a was lower, with isolated yields ranging 908C. Pivalic acid could be employed in equimolar
from 16 to 57%. The lowest yields were obtained with amounts but required 42–100 h reaction times. Thus
aliphatic propargylic alcohols and acetic acid (24– the conditions (5 h at 908C, equimolar amounts of
21%, Table 1, entry 6). This might be in part due to carboxylic acid and propargylic alcohol) described
the fact that those substrates and products are UV in- herein for complex 7c compare well with previously
active, making isolation by column chromatography described catalyst systems.
more difficult. But in general catalysts 7a and 7c
It has been described in the literature that some
showed a remarkable substrate generality, as primary, half-sandwich complexes of ruthenium form their cat-
secondary and tertiary propargylic alcohols could be alytically active species in solution by loss of the p-
converted to the corresponding b-oxo esters. Both ar- cymene ligand.[17a] Mezzetti reported that complexes
omatic and aliphatic propargylic alcohols and carbox- closely related to those described herein lose their p-
ylic acids can be employed in all possible combina- cymene ligand in solution at elevated temperatur-
tions.
es.[18b] The data in Figure 4 clearly show an induction
The complex 7c exhibits activity comparable to the period for the title reaction, suggesting that the initial
other catalysts known to promote this reaction. Wata- step is the formation of the catalytically active species.
nabeꢁs catalyst system was catalytically active in the However, from the data in Table 3 it cannot clearly
conversion of 3-methyl-1-butyn-3-ol and 1-ethynylcy- be concluded that the formation of this species in-
clohexanol to the corresponding b-oxo acetic acid volved arene loss. For both catalysts 7a and 7c, the re-
esters in 54 and 61% yields.[15] The complex [RuCl2
cymene)
ACHTREUNG
ACHTREUNG
2-yn-1-ol and various carboxylic acids to the corre- ent in the reaction mixture.
sponding b-oxo esters in 92–30% yields,[16a] but exhib-
To date we do not have a satisfactory explanation
ited much lower activity with sterically more demand- for why the phosphoramidite complex 7c with N-
ing propargylic alcohols.[16b] As demonstrated in benzyl substituents exhibits better catalytic perfor-
Table 3 and Figure 4, GC yields for 7c and [RuCl
cymene)
parable.
ACHTREUNG
ACHTREUNG
Dixneuf demonstrated that the dimeric complex dation and dimerization reactions of the catalytically
[Ru(m-O2CH)(CO)2(PPh3)]2 exhibited higher activity active metal complexes. However, steric congestion
A
ACHTREUNG
to give the corresponding b-oxo esters from prop-2- cannot be the only cause for the increased reactivity
yn-1-ol and various a-hydroxy carboxylic acids in 69– of 7c compared to 7a, as the isopropyl groups in 7b
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Conversion of Propargylic Alcohols to b-Oxo Esters
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Scheme 5. Stabilizing effect of benzyl groups in phosphoramidite complexes.
and the tert-butyl groups in 11 should have a similar from racemic starting materials as well as little race-
stabilizing effect. On the other hand, Mezzetti report- mization of enantiopure starting material. According-
ed that complex 19 with an architecture similar to 7c ly, Dixneuf reported retention of configuration in his
forms a p-complex 20 upon loss of p-cymene as studies.[16c]
shown in Scheme 5.[18b,22] He also showed that phos-
phoramidites can act as two-, four-, six-, or eight-elec-
tron donors.[22] Arene loss opens free coordination Conclusions
sites, which might initiate catalyst decomposition for
the catalytic systems described herein. For complex In conclusion, this work shows for the first time that
7c, the open coordination site could temporarily be half-sandwich phosphoramidite complexes of rutheni-
occupied by the phenyl group of the N-benzyl sub- um are catalytically active in the formation of b-oxo
stituent as in 20 (Scheme 5). Such an arrangement esters from aromatic and aliphatic primary, secondary
could increase the life time of the catalytically active and tertiary propargylic alcohols and aromatic and
species from 7c in solution, resulting in higher conver- aliphatic carboxylic acids. The atom-economical pro-
sion rates and yields. The methyl groups on the phos- cess is catalyzed with good substrate generality, and
phoramidite ligand in 7a provide less protection than both sterically congested substrates and carboxylic
the N-benzyl groups in 7c. This might result in faster acids in equimolar amounts can be employed in the
catalyst decomposition for 7a, lowering its perfor- reaction. Exclusion of moisture or air is not necessary.
mance.
The ligand structure has a profound impact on the
Watanabe[15] and Dixneuf[16c] have suggested a catalytic activity of the phosphoramidite complexes.
mechanism for the reaction that involves an Ru(h2- The transformation proceeds without racemization of
alkyne) intermediate (Scheme 6). The carboxylic acid a chiral propargylic alcohol, which is in accordance
adds to the triple bond and the resulting enol ester with the previously suggested mechanism for the reac-
complex undergoes an intramolecular transesterifica- tion. Further investigations to better understand the
tion to provide the final product. This mechanism is reactivity and mechanism of the reaction are under-
consistent with the stereochemistry of our reactions. way.
The lack of enantioselectivity might have different
causes, one of which could be a high reaction temper-
ature of 908C. However, assuming the mechanism de- Experimental Section
À
picted in Scheme 6, the C O bond at the stereocenter
would not be cleaved, resulting in racemic products
General remarks and characterization data of the products
can be found in the Supporting Information.
[(R)-BINOL(8H)-N,N-dibenzyl-phosphoramidite]
(2b)
To
a Schlenk flask containing triethylamine (0.25 mL,
1.9 mmol) and dibenzylamine (0.36 mL, 1.9 mmol), toluene
(10 mL) was added followed by phosphorus trichloride
(0.15 mL, 1.7 mmol), which upon addition, yielded a white
smoke. The white slurry was heated to 708C for 12 h during
which the color changed to yellow. After cooling to room
temperature, triethylamine was added (0.5 mL, 3.58 mmol)
followed by (R)-5,5’,6,6’,7,7’,8,8’-octahydro-bi-2-naphthol (6,
0.500 g, 1.70 mmol). Additional 4 mLtoluene were added
and the slurry stirred at room temperature for 24 h. Diethyl
Scheme 6. Proposed mechanism for b-oxo ester forma-
tion.[15,16c]
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Stephen Costin et al.
FULL PAPERS
ether (5 mL) was added and the slurry was filtered over
silica on a 15M frit and the filtrate was dried under oil-
pump vacuum, yielding a white solid. The solid was purified
by flash filtration (1”4 in, silica) using CH2Cl2/hexanes 1:3
to pack/elute. The solvent was removed and the residue
dried in high vacuum affording 2b as a white foam; yield:
0.570 g (1.10 mmol, 65%).
“
A
G
R
To a Schlenk flask containing [RuCl2(p-cymene)]2 (0.144 g,
N
0.235 mmol), a solution of 2b (0.245 g, 0.471 mmol) in
CH2Cl2 (6 mL) was added. The resulting red solution was
stirred at room temperature for 16 h after which the solvent
was removed under high vacuum. Hexanes (5 mL) were
added and the slurry filtered over Celiteꢂ (~1 cm). The
solid was washed with hexanes (30 mL) and the eluent dis-
carded. The product was then washed down using CH2Cl2/
Et2O 9:1 (25 mL) until the Celiteꢂ was no longer red. The
solution was dried under high vacuum, affording 8b as a red
solid; yield: 0.333 g (0.403 mmol, 86%).
“
N
N
phosphoramidite]}” (7a)
To a Schlenk flask containing phosphoramidite 1a (1.123 g,
3.125 mmol), CH2Cl2 (20 mL) was added followed by [RuCl2
(p-cymene)]2 (0.990 g, 1.62 mmol) to obtain a dark red solu-
tion. The solution was allowed to stir under a nitrogen at-
mosphere at room temperature for 2.5 h, and then the sol-
vent was removed under oil-pump vacuum, yielding a red
solid. Isopropyl alcohol (5 mL) was added and the solid was
collected by filtration over a medium frit (10–15M). It was
then washed with isopropyl alcohol (2”1 mL) and dried
under vacuum affording 7a as a red solid; yield: 1.988 g
(2.987 mmol, 96%).
“(R)-BIPHEN-N,N-dimethyl-phosphoramidite” (10)
To a Schlenk flask containing (R)-5,5’,6,6’-tetramethyl-3,3’-
di-tert-butyl-1,1’-biphenyl-2,2’-diol
[“(R)-BIPHEN’’,
9]
(0.217 g, 0.613 mmol), toluene (6 mL) was added followed
by hexamethylphosphorus triamide (0.14 mL, 0.77 mmol)
and NH4Cl (0.010 g). The clear solution was heated at
1008C for 12 h under nitrogen atmosphere. Upon cooling
the solvent was removed and the solid was dried under oil-
pump vacuum. Diethyl ether (2 mL) was added to the white
residue and the resulting suspension was cooled to À188C
for 1 h and then filtered over a medium frit (10–15M). The
solid was washed with cold diethyl ether (2”1 mL). The fil-
trate was concentrated under vacuum to 1 mLand stored at
À188C for 1 h. The suspension was filtered over a medium
frit again and both crops were dried under oil-pump vacuum
to give 10 as a white solid; yield: 0.160 g (0.374 mmol, 61%).
“
N
N
phosphoramidite]}” (7b)
To a Schlenk flask containing 1b (0.212 g, 0.510 mmol),
CH2Cl2 (8 mL) was added followed by [RuCl2(p-cymene)]2
E
(0149 g, 0.243 mmol) and the solution turned dark red. The
solution was allowed to stir under nitrogen for 18 h. Solvent
was removed under oil-pump vacuum, yielding a red solid.
The crude product was flash chromatographed (1”4.5 in,
silica, CH2Cl2/diethyl ether, 49:1 v/v). Upon drying under
oil-pump vacuum, 7b was obtained as a red solid; yield:
0.232 g (0.326 mmol, 67%).
“
N
N
phosphoramidite]}” (11)
To a Schlenk flask containing 10 (0.145 g, 0.339 mmol),
ClCH2CH2Cl (5 mL) was added and the solid dissolved.
“
A
G
[RuCl2(p-cymene)]2 (0.099 g, 0.162 mmol) was then added
N
phosphoramidite]}” (7c)
and the resulting red solution was refluxed under a nitrogen
atmosphere for 2.5 h. The solvent was removed and the
dark red solid was dried under oil-pump vacuum and then
extracted with diethyl ether (3”2 mL). The solvent was re-
moved from the extracts and the product was dried under
oil-pump vacuum to give 11 as a purple solid; yield: 0.143 g
(0.195 mmol, 60%).[19]
To a Schlenk flask containing 1c (0.250 g, 0.489 mmol),
CH2Cl2 (5 mL) was added followed by [RuCl2(p-cymene)]2
G
(0.150 g, 0.245 mmol) and the solution turned dark red. The
solution was allowed to stir under nitrogen for 18 h. Solvent
was removed under oil-pump vacuum, yielding a red solid.
The crude product was purified by flash filtration over 1”5
in, silica, using CH2Cl2/Et2O 9:1 to pack/elute; the red band
was collected. Upon drying under oil-pump vacuum, 7c was
obtained as a red solid; yield: 0.351 g (0.429 mmol, 88%).
“
N
N
phosphoramidite]}” (12)
To a Schlenk flask containing 1b (0.100 g, 0.241 mmol),
“
A
G
U
CH2Cl2 (5 mL) was added followed by [RuCl2(C6Me6)]2
A
dimethyl-phosphoramidite]}” (7d)
(0.080 g, 0.120 mmol) and the solution turned dark red-
brown. The solution was refluxed under nitrogen for 6 h.
Solvent was removed under oil-pump vacuum, yielding an
orange solid. The crude product was washed with 2”4 mL
dry Et2O and the solvent decanted. Upon drying under oil-
pump vacuum, 12 was obtained as an orange solid; yield:
0.140 g (0.187 mmol, 78%) in 95% spectroscopic purity.[19]
To a Schlenk flask containing 1d (0.206 g, 0.398 mmol),
CH2Cl2 (3 mL) was added followed by [RuCl2(p-cymene)]2
E
(0.111 g, 0.181 mmol) to obtain a dark red solution. The so-
lution was allowed to stir under nitrogen atmosphere at
room temperature for 2.5 h, and then the solvent was re-
moved under oil-pump vacuum, yielding a red solid. Diethyl
ether (2”2.5 mL) was added and the resulting slurry was
stirred and the solvent decanted. The solid was then dried
under vacuum affording 7d as a red solid; yield: 0.198 g
(2.99 mmol, 66%).
2422
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Adv. Synth. Catal. 2008, 350, 2414 – 2424

Conversion of Propargylic Alcohols to b-Oxo Esters
FULL PAPERS
References
Typical Procedure for Catalytic Experiments
In a screw-capped vial, 2-phenyl-3-butyn-2-ol (3e, 0.100 g,
0.684 mmol) and benzoic acid (4a, 0.084 g, 0.688 mmol)
were dissolved in cyclohexane (3 mL). The catalyst (7c)
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in a heating mantle preheated to 908C. After 5 h all volatiles
were removed from the sample and the residue was purified
by flash chromatography (silica, CH2Cl2/cyclohexane, 2:1 v/v)
to obtain the product 5m as a yellow oil; yield: 0.146 g
(0.544 mmol, 79%).
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1
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Acknowledgements
We thankthe University of Missouri – St. Louis for support.
Funding from the National Science Foundation for the pur-
chase of the ApexII diffractometer (MRI, CHE-0420497), the
purchase of the NMR spectrometer (CHE-9974801) and the
purchase of the mass spectrometer (CHE-9708640) is ac-
knowledged. We thank Prof. Frederick Sweet (Washington
University in St. Louis) for the generous donation of some
laboratory equipment and Prof. Rudolph Winter (University
of Missouri – St. Louis) for fruitful discussions.
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