Ruthenium catalyzed decarbonylative arylation at sp3 carbon centers in pyrrolidine and piperidine heterocycles

Article abstract of DOI:10.1021/ja072577n

This paper describes the development of a new catalytic transformation, the ruthenium-catalyzed decarbonylative arylation of cyclic 2-amino esters, which replaces the ester group with an aryl ring at the sp³ carbon center. For example, proline ester amidine 1 is converted to 2-arylpyrrolidine 3 in the presence of arylboronic acids or esters as arene donors and Ru ₃(CO)₁₂ as the catalyst. This process provides a rapid access to a variety of 2-arylpyrrolidines and piperidines from commercially available proline, hydroxyproline, and pipecolinate esters. The examination of the substrate scope also showed that many arene boronic acids and boronate esters serve as coupling partners. The high chemoselectivity of this process was demonstrated and ascribed to the significant rate difference between the decarbonylative arylation and the C-H arylation. The decarbonylative arylation complements the C-H arylation, since the latter process lacks control over the extent of functionalization, affording a mixture of mono- and bis-arylpyrrolidines. When applied in tandem, these two processes provide 2,5-diarylpyrrolidines in two steps from the corresponding proline esters. It was also demonstrated that the required amidine or iminocarbamate directing group fulfills two major functions: first, it is essential for the ester activation step, which occurs via the coordination-assisted metal insertion into the acyl C-O bond; second, it facilitates the decarbonylation, via the stabilization of a metallacycle intermediate, assuring the formation of the 2-arylated products instead of the corresponding ketones observed before by others.

Full text of DOI:10.1021/ja072577n

Published on Web 09/06/2007
Ruthenium Catalyzed Decarbonylative Arylation at sp3 Carbon
Centers in Pyrrolidine and Piperidine Heterocycles
Denis V. Gribkov, Stefan J. Pastine, Michael Schnu¨rch, and Dalibor Sames*
Contribution from the Department of Chemistry, Columbia UniVersity, New York,
New York 10027
Received April 12, 2007; E-mail: sames@chem.columbia.edu
Abstract: This paper describes the development of a new catalytic transformation, the ruthenium-catalyzed
decarbonylative arylation of cyclic 2-amino esters, which replaces the ester group with an aryl ring at the
sp3 carbon center. For example, proline ester amidine 1 is converted to 2-arylpyrrolidine 3 in the presence
of arylboronic acids or esters as arene donors and Ru3(CO)12 as the catalyst. This process provides a
rapid access to a variety of 2-arylpyrrolidines and piperidines from commercially available proline,
hydroxyproline, and pipecolinate esters. The examination of the substrate scope also showed that many
arene boronic acids and boronate esters serve as coupling partners. The high chemoselectivity of this
process was demonstrated and ascribed to the significant rate difference between the decarbonylative
arylation and the C-H arylation. The decarbonylative arylation complements the C-H arylation, since the
latter process lacks control over the extent of functionalization, affording a mixture of mono- and
bis-arylpyrrolidines. When applied in tandem, these two processes provide 2,5-diarylpyrrolidines in two
steps from the corresponding proline esters. It was also demonstrated that the required amidine or
iminocarbamate directing group fulfills two major functions: first, it is essential for the ester activation step,
which occurs via the coordination-assisted metal insertion into the acyl C-O bond; second, it facilitates
the decarbonylation, via the stabilization of a metallacycle intermediate, assuring the formation of the
2-arylated products instead of the corresponding ketones observed before by others.
Introduction
As a mechanistic rationale for this transformation, we propose
that the reaction is initiated by the directing group-assisted
insertion of ruthenium metal into the acyl-O bond of the ester,
forming an acyl-metal-alkoxide complex, which undergoes
CO extrusion to afford the key intermediate alkoxide 5a (Figure
1). A similar intermediate is also formed in the C-H arylation
pathway, via the sequential metal insertion into the C-H bond
and ketone insertion into the metal hydride. Thus, both pathways
converge at the point of the alkyl-alkoxide complex 5a/5b,
which participates in transmetallation with phenyl boronate ester
and reductive elimination to yield the product 6 (Figure 1).
Activation of carboxylic esters via transition metal insertion
into the acyl carbon-oxygen bond has been demonstrated and
utilized in catalytic transformations of these common functional
groups.5 Most notably, 2-pyridinylmethyl esters can be converted
to the corresponding ketones via the coupling with arene
boronate esters in the presence of Ru3(CO)12 as the catalyst.
Similarly, ruthenium-catalyzed reductive decarboxylation of
these esters was reported with ammonium formate or silane as
the reducing agents.6 The importance of the pyridine ring for
the chelation-assisted activation of the ester was demonstrated.
Saturated cyclic amines are indispensable building units of
biologically active compounds, including alkaloids, pharma-
ceuticals, and research probes.1 Accordingly, many different
approaches to the functionalization of these systems via C-H
bond cleavage have been developed, utilizing a wide spectrum
of known chemical reactivity.2 However, with the exception of
carbene insertion chemistry,3 there are only a few examples of
catalytic methods based on homogeneous transition metal
complexes.2
We have recently reported the ruthenium-catalyzed arylation
of sp3 C-H bonds at the R-position of saturated cyclic amines
with aryl boronates as arene donors.4 In the course of exploring
the scope of this method, we discovered a new catalytic
transformation, the decarbonylative arylation of esters at sp3
carbon centers. Specifically, subjection of the proline ester
amidine 1 to the C-H arylation protocol did not lead to the
formation of product 2, but instead resulted in the replacement
of the carboxylate moiety with the phenyl ring, affording
R-phenyl amidine 3a as the major product (Scheme 1).
(1) 2-Arylpyrrolidines and piperidines exhibit potent biological activity,
particularly in the CNS. For examples, see: Elliot, R. L.; Kopeka, H.; Lin,
N.-H.; He, Y.; Garvey, D. S. Synthesis 1995, 772-774.
(2) For an excellent recent review, see: Campos, K. R. Chem. Soc. ReV. 2007,
36, 1069-1084.
(5) Lin, Y.-S.; Yamamoto, A. In ActiVation of UnreactiVe Bonds and Organic
Synthesis; Murai, S., Ed.; Springer: Berlin, Germany 1999; pp 161-192.
(6) (a) Chatani, N.; Tatamidani, H.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem.
Soc. 2001, 123, 4849-4850. (b) Tatamidani, H.; Yokota, K.; Kakiuchi,
F.; Chatani, N. J. Org. Chem. 2004, 69, 5615-5621. (c) Ruthenium-
mediated decarbonylation of methyl benzoate (unactivated ester) has been
reported: Hiraki, K.; Kira, S.; Kawano, H. Bull. Chem. Soc. Jpn. 1997,
70, 1583-1592.
(3) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. J. Am.
Chem. Soc. 2003, 125, 6462-6468.
(4) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128,
14220-14221.
9
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J. AM. CHEM. SOC. 2007, 129, 11750-11755
10.1021/ja072577n CCC: $37.00 © 2007 American Chemical Society

Ru-Catalyzed Decarbonylative Arylation of sp3 C Centers
A R T I C L E S
Scheme 1. Decarbonylative Arylation Proceeds in Preference to the C-H Arylation
Figure 1. Proposed mechanistic rationale for the new decarbonylative arylation at sp3 carbon centers and its relationship to the sp3 C-H arylation. Both
transformations access a similar metal alkoxide intermediate (e.g., 5a/5b), which undergoes transmetallation and C-C bond formation to afford the product
(e.g., 6).
Also, palladium-catalyzed couplings of activated carboxylate
esters with arylboronate esters, to produce aryl ketones,7,8 and
with alkenes, to afford the Heck coupling products, were
reported.9 Moreover, carboxylic anhydrides as activated sub-
strates were reported to undergo decarbonylative arylation with
arene boronates and other arene donors.10
The catalytic decarboxylative transformation of allyl- and
benzyl-esters belongs to a mechanistically distinct class of
reactions, initiated by the cleavage of the C-O bond linking
the allyl group and acyloxy moiety, leading to a loss of CO2
and formation of new C-C bonds.11 Catalytic cross-couplings
of free arene carboxylic acids with haloarenes and alkenes have
recently been reported; these reactions also proceed via a
decarboxylative mechanism.12
To the best of our knowledge, the decarbonylative arylation
disclosed here represents a new catalytic transformation, achiev-
ing a direct substitution of an unactivated ester with an aryl
ring at the sp3 carbon center. From a synthetic perspective, this
reaction enables regioselective preparation of mono-arylated
nitrogen heterocycles starting from readily available cyclic
R-amino esters (e.g., proline, hydroxyproline, pipecolinic acid
esters) and, thus, complements the C-H arylation method which
provides a mixture of mono- and bis-arylated products (Figure
2). The “overfunctionalization” of substrates containing two
C-H bonds of similar reactivities is a common problem of many
catalytic directed C-H functionalization processes, developed
for both aromatic and saturated substrates.13 The significant
difference in rates between the decarbonylative arylation and
the C-H arylation allows for selective synthesis of mono-
arylated amines and thus represents a promising alternative for
the preparation of these compounds under neutral catalytic
conditions. In the following pages, we describe the development
and the scope of this transformation.
Results
Optimization of Reaction Conditions and Arene Donor
Substrate Scope. Guided by the mechanistic rationale provided
above, the reaction conditions were optimized. With regard to
the catalyst, only low-valent ruthenium complexes afford the
desired product. Ru3(CO)12 is the best catalyst; RuH2(CO)-
(PPh3)3 is less effective, showing lower reaction rates as well
as side product formation. In accord with the mechanistic
proposal, the ketone reagent (required for the C-H arylation
process, Figure 1) is not needed. Both arylboronic acids and
esters can be used as coupling partners. The best results for
arylation with arylboronate esters are achieved in m-xylene at
130 °C employing 1 equiv of ester; under these conditions, the
reaction is completed within several hours. Arylation with
arylboronic acids gave the best results when performed in DMF
employing a slight excess of acid (1.1 equiv). However, there
was no clear trend in yields when using arylboronic acids. For
example, phenyl-, 4-fluorophenyl-, and 4-(dimethylamino)-
phenylboronic acids gave yields superior to those obtained with
corresponding neo-pentanediol derived esters (Table 1, forma-
tion of 3a, 3b, 3f), whereas 4-(trifluoromethyl)phenyl- and
indole-5-boronic acids (Table 1, formation of 3d, 3k) gave
inferior amounts of arylation products. These results can be
attributed to differences in stability between free boronic acids
and esters under the reaction conditions. Importantly, since CO
is released as a byproduct, the reaction shows lower efficiency
when conducted in lower boiling solvents, such as dioxane or
(7) (a) Kakino, R.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn. 2001,
74, 371-376. (b) Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett. 2004,
6, 3597-3599.
(8) For synthesis of ketones via palladium-catalyzed coupling of thioesters and
boronic acids, see: Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000,
122, 11260-11261.
(9) Gooâen, L. J.; Paetzold, J. Angew. Chem., Int. Ed. 2002, 41, 1237-1241.
(10) (a) Gooâen, L. J.; Paetzold, J. AdV. Synth. Catal. 2004, 346, 1665-1668.
(b) O’Brien, E. M.; Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2003, 125,
10498-10499.
(11) (a) Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002-
10003. (b) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127,
13510-13511 and references therein. (c) Mohr, J. T.; Nishimata, T.;
Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348-11349.
(d) Kuwano, R.; Yokogi, M. Chem. Commun. 2005, 5899-5901.
(12) (a) Catalytic decarboxylative arylation of free carboxylic acids with
haloarenes has recently been reported: Forgione, P.; Brochu, M.-C.; St-
Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc.
2006, 128, 11350-11351. (b) Gooâen, L. J.; Deng, G.; Levy, L. M. Science
2006, 133, 662-664. Catalytic cross-coupling of free arene carboxylic acids
with alkenes (decarboxylative olefination): (c) Myers, A. G.; Tanaka, D.;
Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250-11251. (d) Tanaka,
D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323-
10333.
(13) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077-1101.
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A R T I C L E S
Gribkov et al.
Figure 3. Cyclic amidine is a superior directing group.
under the standard conditions, a good yield of the product was
obtained by performing the reaction in a microwave reactor at
180 °C. Introduction of the more sterically encumbered mesityl
ring failed. Also, an ortho-fluoro substituent was not tolerated.
Small quantities of the reductive decarboxylation product
5-pyrrolidin-1-yl-3,4-dihydro-2H-pyrrole and the 1,5-bis-ary-
lated material were detected in some reaction mixtures (<5%
by GC). As expected, addition of an excess of aryl boronate
resulted in an increased amount of bis-arylated byproducts,
formed by the C-H arylation of the product (see above, Figure
2).4 Bis-arylated products are not formed in the case of
arylboronic acids. Interestingly, the reaction rate and yield were
significantly affected by the nature of the ester backbone of the
aryl donor (between pinacol- and neo-pentanediol-derived
esters), however, in an irregular manner. For example, formation
of product 3a was approximately ten times slower using the
pinacol-derived ester compared to the neopentanediol-derived
substrate. In contrast, the synthesis of 3i was more efficient with
the pinacol-derived boronate.
Figure 2. Significant rate difference between the decarbonylative arylation
and the C-H arylation enables synthesis of mono-arylated products.
Formation of bis-substituted side products is a shortcoming of many catalytic
directed C-H functionalization methods. DG ) directing group.
Table 1. Decarbonylative Arylation of Methyl Prolinate 1a
Directing Groups and R-Amino Ester Substrates. The
Scope. The amidine group proved to be far superior to other
commonly employed directing groups. The corresponding
carbamates and amides gave <10% of the arylation product,
presumably due to the lower coordination ability of these groups
compared to the cyclic amidine (Figure 3).
The next key issue was whether the decarbonylative arylation
protocol could be applied to other saturated heterocyclic esters
with particular focus on six-membered cyclic substrates. The
ethyl ester of piperidine-2-carboxylate is commercially available,
however we were unable to prepare the requisite amidine starting
material due to its instability (caused by intramolecular attack
of the ester by the amidine nitrogen). A search for a viable
directing group identified the 4,4-dimethyl-4,5-dihydro-1,3-
oxazolyl moiety as a suitable candidate. The corresponding ethyl
pipecolinate derivative 7 was prepared in high yield (see
Supporting Information) and submitted to the reaction condi-
tions. Gratifyingly, this new substrate underwent the decarbo-
nylative arylation, affording products 8a-d in yields comparable
to those obtained with the proline-based substrates (Scheme 2);
however, longer reaction times were necessary. Reductive
decarboxylation of 7 was identified as a major side reaction,
yielding the corresponding piperidine in 10-20%. The better
stability and lower reactivity of substrate 7 can in major part
be ascribed to the lower basicity of the iminocarbamate in
comparison to the amidine group. Presumably for the same
reason, the aryl donor containing a dimethylamino group
required a higher reaction temperature (8d) while the pyridyl
boronates gave no desired products at all. Phenylboronic acid
was substantially less effective than the corresponding boronate
ester (Scheme 2, formation of 8a), due to the lower stability of
the acids under prolonged heating in the reaction medium.
The decarbonylative arylation of substrates derived from
methyl piperazine-2-carboxylate also gave the desired products,
although at higher catalyst loading and higher temperature when
compared to piperidine and pyrrolidine substrates (Scheme 3).
a Coupling with boronate esters: 0.9-1 equiv of ester (neo-pentanediol
derived unless otherwise stated), xylene; yields are based on esters. Coupling
with arylboronic acids: 1.1 equiv of acid, DMF; yields are based on
b
amidines and given in parentheses. Performed in a microwave reactor at
180 °C for 30 min. cPinacol-derived ester used. dReaction time 18 h.
eReaction time 48 h.
toluene, which necessitates the use of a sealed vessel. With the
optimized procedure in hand, we examined the scope of the
new transformation beginning with the arene boronate substrates
(Table 1).
The present method is compatible with a variety of aryl and
heteroaryl boronate ester donors. The electronic nature of the
boronates had no significant effect on the efficiency of the
transformation. Specifically, aryl boronates containing both
electron-withdrawing substituents (F, Cl, CF3) and electron-
donating counterparts (OMe, NMe2) were successfully coupled
with small differences in the yield or reaction time. Notably,
pyridine donors, capable of coordinating to the ruthenium metal
and competing with the amidine directing group, were well
tolerated (compounds 3i, 3j). Although the coupling with ortho-
substituted boronic ester to form 3g was considerably slower
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Ru-Catalyzed Decarbonylative Arylation of sp3 C Centers
A R T I C L E S
Scheme 2. Decarbonylative Arylation of Ethyl Pipecolinate
Substrate
arylation protocol. In this case, phenyl ketone 16 was formed
in 53% yield with no detectable amounts of the decarbonylated
arylation product (Scheme 4). Also, no C-H arylation product
was detected. Apparently, the steric hindrance at C-2 prevents
the decarbonylation and formation of a tertiary carbon-
ruthenium bond; instead, the acyl-ruthenium-alkoxide inter-
mediate undergoes the transmetallation to furnish the phenyl
ketone. This result supports the mechanistic proposal where the
ester activation is facile while the subsequent step(s) (either the
transmetallation or reductive elimination) is slow. In stark
contrast, the related C-H arylation is initiated by the slow C-H
insertion step (Figure 1). This hypothesis explains the dramatic
differences between these transformations; the C-H arylation
of symmetrical substrates (e.g., pyrrolidine-amidine) affords a
mixture of mono- and bis-arylation products, and the unsym-
metrical â-substituted substrates (e.g., 3-hydroxypyrrolidine-
derived substrate) give a mixture of mono-arylated regioisomers
in addition to the bis-arylated product.
a Performed with phenylboronic acid in DMA; GC yield. bPerformed at
140 °C; 1.5 equiv of boronate ester used. cReaction conditions: DMA,
150 °C, 15 h.
Scheme 3. Decarbonylative Arylation of Methyl
Piperazine-2-carboxylate Derivatives
From the synthetic angle, the decarbonylative arylation
complements the C-H arylation method by addressing its
shortcomings related to the “overfunctionalization”. When
applied in a sequential manner, these two methods enable two-
step preparation of unsymmetrical 2,5-bis-arylpyrrolidines
(Scheme 5). Both the amidine and the iminocarbamate products
can be efficiently cleaved to yield the free amines by treatment
with NH2NH2/AcOH or NH2NH2/TFA at elevated temperatures
(see Supporting Information). Notably, the deprotection proce-
dures are compatible with a commonly employed TBS protect-
ing group.
a NMR yield; concomitant formation of corresponding 2,3-dehydroge-
nated product observed.
Scheme 4. Catalytic Arylation Is Chemoselective
Stereochemical Issues. In addition to the high chemoselec-
tivity of the arylation reaction, it is also compatible with chiral
centers in the 4-position (Scheme 4 and Table 2). However,
the process is not stereoselective at the 2-position. The epimer-
ization of the ester-bearing center occurs at the stage of directing
group installation as elucidated in the preparation of hydrox-
yproline derivatives 13 and 17 (Table 2). The crude reaction
mixture resulting from heating a single diasteromer of the
O-protected hydroxyprolinate ester with 5-methoxy-3,4-dihydro-
2H-pyrrole consisted of nearly an equimolar ratio of diastere-
omers of the corresponding product (see Supporting Information;
optically pure methyl prolinate was also racemized during the
preparation of the amidine substrate). Moreover, diastereomeric
hydroxyproline derivatives (cis-13, trans-13) underwent inter-
conversion on silica gel or even upon standing at room
temperature. Interestingly, the benzyl protected analogues (cis-
17, trans-17) showed no epimerization at ambient temperature,
and each isomer could be obtained diastereomerically pure Via
column chromatography.
The low reactivity and the relative facility of undesired
competitive pathways (reductive decarbonylation and elimina-
tion) account for low efficiency. Again, the presence of an amino
group in the starting material (e.g., 10) led to a significant
inhibition of the reaction. Despite the modest yields, these are
encouraging results as the catalytic C-H arylation of piperazine
substrates has hitherto failed completely. The arylation of the
corresponding acyclic amino ester substrates was also unsuc-
cessful.
Nevertheless, amidines 13 and 17 can be arylated using the
developed protocol in good yields, providing a mixture of cis
and trans isomers that are readily separable Via column
chromatography (Table 2). The trans/cis ratio of products 14a-c
obtained by the arylation of the diastereomeric mixture 13
ranged from 1.3:1 to 1.9:1. In the arylation of diastereomerically
pure compound (2S,4R)-17 (trans), the corresponding ratio was
increased to 2.8:1 (entry 5). When the other diastereomer
(2R,4R)-17 (cis) was used, the ratio decreased to almost an
equimolar level (entry 6). This trend suggests that the arylation
process itself may be stereospecific if the competitive thermal
epimerization of the substrate could be minimized.
Selectivity of the Decarbonylative Arylation. The high
chemoselectivity of the arylation process was demonstrated by
the conversion of compound 13 (a 1:1 mixture of diastereomers)
to product 14 (Scheme 4 and Table 2). No other regioisomers
or bis-arylated compounds were detected in the reaction mixture.
Also, the chiral center at the 4-position (carbon bearing the
TBSO-group) was intact (the stereochemistry in the 2-position
will be discussed below). We also examined the arylation at a
tertiary center by submitting 2-methylprolinate ester 15 to the
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A R T I C L E S
Gribkov et al.
Table 2. Decarbonylative Arylation of Hydroxyproline Derivatives
b
c
a >99% ee as determined Via Mosher’s amide. Performed with 1.1 equiv of phenylboronic acid in DMF. 93% ee as determined Via Mosher’s amide.
dPerformed at 140 °C for 2 h.
Scheme 5. Sequential Arylation of Pyrrolidine Systemsa,b
Scheme 6. Proposed Mechanism for the Reaction of Esters with
Aryl Boronates Catalyzed by Ru3CO12
a Decarbonylative arylation complements the C-H arylation method.
bConditions: (a) Ru3CO12 (5 mol %), xylene or DMF, 130 °C. (b) Ru3CO12
(3.3 mol %), pinacolone, 150 °C. (c) NH2NH2/AcOH or NH2NH2/TFA,
ethanol, 120 or 140 °C.
In summary, the decarbonylative arylation of esters 13 and
17 enables a facile preparation of both the cis and trans series
of 4-hydroxy-2-aryl-pyrrolidine derivatives from a single pre-
cursor.
Mechanistic Proposal. The Key Role of the Directing
Group. We propose the following mechanistic hypothesis that
is consistent with both the results described in this paper and
the ideas put forth by others (Scheme 6).6-8 The catalytic process
is initiated by the activation of the ester, via insertion of
ruthenium into the acyl-O bond, promoted by coordination of
the metal to the directing group. The resulting acyl, alkoxo-
ruthenium complex III may undergo transmetallation with
phenyl boronate to produce acyl, aryl-ruthenium intermediate
IV along with trialkyl borate, which is followed by reductive
elimination, to furnish ketone product VII. Indeed, an analogous
mechanistic sequence was proposed by Chatani and colleagues
for the preparation of ketones from esters containing the
pyridine-directing group appended to the carboxylic oxygen (19
f 20, Scheme 7).6
However, complex III may undergo decarbonylation, result-
ing in the formation of new intermediate VIII, which would
proceed via transmetallation and reductive elimination to furnish
the R-arylation product VI. The latter pathway is favored in
the presence of a strongly coordinating directing group, such
as the amidine group described here, due to the stabilization of
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Ru-Catalyzed Decarbonylative Arylation of sp3 C Centers
A R T I C L E S
Scheme 7. Importance of Directing Group
equiv of CO was released in the course of the arylation. We
also confirmed that the ketone is not an intermediate in the
decarbonylative arylation process (Supporting Information).
Conclusions
In this paper, we described the discovery and development
of catalytic decarbonylative arylation of cyclic R-amino esters.
This process provides rapid access to a variety of 2-arylpyrro-
lidines and piperidines from commercially available proline or
picolinic acid derivatives in a selective manner. This reaction
is complementary to the recently introduced sp3 C-H arylation
process, as it addresses one key shortcoming of the latter
process, poor control over the extent of C-H functionalization
(mono- and bis-arylation) and the regioselectivity (with unsym-
metrical substrates). Applied in tandem, the decarbonylative
arylation and the C-H arylation enable the synthesis of 2,5-
diarylpyrrolidines from proline derivatives.
The product formation analysis afforded evidence that sup-
ports the proposed mechanistic hypothesis where the catalytic
cycle is initiated by chelation-assisted ester activation, followed
by decarbonylation and transmetallation of the respective
intermediates, to ultimately produce the R-arylated product and
regenerated catalyst. The critical importance of a strong directing
group was demonstrated, facilitating not only the ester activation
but also the decarbonylation, and thus assuring the formation
of the R-arylated product instead of the ketone. This insight
may be useful for the future design of catalytic arylation
methods.
the five-membered metallacycle intermediate VIII (assuming
that the ruthenium cluster fragments to mononuclear ruthenium
catalyst). It should be noted that product VI could also be
accessed via intermediate IV, that is, via a sequence where the
transmetallation precedes the decarbonylation. Either way, the
directing group fulfills seVeral major roles; it is crucial for the
ester actiVation, but it also affects the product distribution.
To further support this proposal, we prepared esters 21 and
23 with the goal of separating the ester activation from the
metallacycle stabilization by installing two directing groups
(Scheme 7). Remarkably, the carbamate-protected substrate 21
gave ketone 22 as the only islolated product, while the amide-
protected substrate furnished the 2-phenylpyrrolidine compound
24. A seemingly small structural change led to a complete switch
in the reaction outcome. These observations are consistent with
the known trends: namely, carbamates are weaker directing
groups than amides due to the weaker coordination to transition
metals.
Acknowledgment. This work was supported by NIGMS and
Bristol-Myers Squibb (the Unrestricted Grants in Synthetic
Organic Chemistry Award). Michael Schnu¨rch would like to
thank the Austrian Science Foundation (FWF) for the Erwin
Schro¨dinger postdoctoral fellowship.
Supporting Information Available: Experimental protocols
and spectral characterization of discussed compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Currently, there is no structural information available for the
active metal species because all attempts to isolate relevant
intermediates have so far been unsuccessful. The global mech-
anism is supported by volumetric analysis that showed that 1
JA072577N
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