Synthesis of enantiomerically enriched imidazolidin-2-ones through asymmetric palladium-catalyzed alkene carboamination reactions

Article abstract of DOI:10.1002/anie.201205233

Positive water effect: A catalyst composed of [Pd₂(dba) ₃] (dba=dibenzylideneacetone) and (S)-Siphos-PE is effective for the enantioselective coupling of N-allyl ureas with aryl bromides to afford 4-substituted imidazolidin-2-ones. Added water leads to significantly improved enantioselectivities with electron-poor aryl halide substrates. It is suggested that the C-C bond-forming reductive elimination is the enantiodetermining step in these reactions. Copyright

Full text of DOI:10.1002/anie.201205233

Angewandte
Chemie
DOI: 10.1002/anie.201205233
Asymmetric Catalysis
Synthesis of Enantiomerically Enriched Imidazolidin-2-Ones through
Asymmetric Palladium-Catalyzed Alkene Carboamination
Reactions**
Brett A. Hopkins and John P. Wolfe*
Chiral 4-substituted imidazolidin-2-ones are displayed in
a myriad of biologically active compounds, including potent
HIV protease inhibitors.[1] However, despite their signifi-
cance, the preparation of these compounds by asymmetric
catalysis has rarely been reported.[2] In addition, no existing
catalytic asymmetric reaction allows for the generation of
promising result, a survey of other phosphine and phosphor-
amidite ligands did not lead to further improvements in
asymmetric induction.
À
a C C bond during the course of imidazolidin-2-one forma-
tion. Most other routes to enantiopure imidazolidin-2-ones
involve the synthesis of chiral 1,2-diamines, which often
requires several synthetic steps and can be particularly
lengthy when the two amino groups bear different substitu-
ents.[3,4]
Here we describe the first catalytic asymmetric alkene
carboamination reactions between N-allyl urea derivatives
and aryl or alkenyl halides.[5,6] These reactions provide
a simple route to enantiomerically enriched 4-(arylmethyl)-
imidazolidin-2-ones, and these studies illustrate the utility of
water as an additive in an enantioselective Pd-catalyzed
alkene difunctionalization reaction. Moreover, the results of
In efforts to both increase the asymmetric induction in Pd/
(S)-Siphos-PE-catalyzed carboamination reactions of N-allyl
ureas, and to explore the effect of nitrogen nucleophilicity on
asymmetric induction, we prepared a series of substrates
bearing different aromatic groups on the cyclizing nitrogen
atom. As shown in Table 1, the level of asymmetric induction
increased with the increasing electron-withdrawing ability of
the p-substituent on the N-aryl moiety of 1. Unfortunately,
the chemical yields also decreased due to the diminished
reactivity of these substrates, and unreacted starting material
was observed in crude reaction mixtures. To address this
À
these experiments suggest that C C bond-forming reductive
elimination may be the enantiodetermining step in trans-
formations of N-allyl urea substrates. This contrasts with
other asymmetric metal-catalyzed alkene carboamination
reactions, in which the absolute stereochemistry appears to
be set during alkene aminometalation.[7]
Our prior studies on Pd-catalyzed asymmetric carboami-
nations of N-Boc-pent-4-enylamine (Boc = tert-butoxycar-
bonyl) demonstrated that use of (R)-Siphos-PE[8] as a ligand
provides 2-benzylpyrrolidine derivatives with good levels of
enantioselectivity.[7a] Thus in our efforts to generate enantio-
merically enriched imidazolidin-2-ones we initially examined
the use of a catalyst composed of [Pd2(dba)3] (dba = diben-
zylideneacetone) and (R)-Siphos-PE for the asymmetric
conversion of 1b to 2b. Unfortunately, this catalyst provided
2b in only modest enantioselectivity [Eq. (1)].[9] However, we
were gratified to find that the diastereomeric ligand (S)-
Siphos-PE provided 2b in 93% yield and 79% ee. Despite this
Table 1: Electronic effects.[a]
Entry
X
Yield [%][b]
ee [%]
1
2
3
4
N(Bn)Me (1a)
OMe (1b)
H (1c)
Br (1d)
CN (1e)
70 (2a)
93 (2b)
90 (2c)
45 (2d)
46 (2e)
87 (2e)
81 (2 f)
73
79
78
83
89
86
92
[*] B. A. Hopkins, Prof. Dr. J. P. Wolfe
Department of Chemistry, University of Michigan
930 N. University Ave, Ann Arbor, MI 48109-1055 (USA)
E-mail: jpwolfe@umich.edu
5
6[c]
7[c]
CN (1e)
NO2 (1 f)
[**] The authors acknowledge the NIH-NIGMS (GM 098314) for
financial support of this work. Additional funding was provided by
GlaxoSmithKline and Amgen. The authors thank Dr. Duy N. Mai for
conducting preliminary experiments.
[a] Conditions: 1.0 equiv 1, 2.0 equiv p-tBu-C6H4-Br, 2.0 equiv NaOtBu,
2 mol% [Pd2(dba)3], 6 mol% (S)-Siphos-PE, toluene (0.2m), 908C, 12 h.
[b] Yield of isolated products (average of two or more runs). [c] The
reaction was conducted at 1208C in xylenes.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205233.
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problem the reaction temperature was increased to 115–
1208C, and the desired products were generated in good
chemical yield (entries 6 and 7) without a significant decrease
in asymmetric induction.[10] The best result was obtained with
p-nitrophenyl-substituted substrate 1 f, which was converted
to 2 f in 81% yield and 92% ee.
In order to explore the scope of the asymmetric carbo-
amination reactions, substrate 1 f was coupled with a range of
different aryl halide electrophiles (Table 2). We initially
impact on the reaction of 1 f with 4-bromoanisole, but
addition of 40 mol% of trifluoroacetic acid provided results
superior to those obtained with either added water or no
additive (entry 13). Efforts to employ alkenyl halides as
electrophiles in the asymmetric carboamination of 1 f were
unsuccessful. However, the reaction of substrate 1e with 2-
bromovinyltrimethylsilane proceeded in 65% yield and 86%
ee (entry 15). The coupling of 1e with aryl bromides
generated cyclic urea products with lower enantioselectivies
than were obtained in analogous reactions of 1 f (entries 16–
20). Use of aryl iodides as electrophiles in reactions of 1e and
1 f led to diminished enantioselectivities as compared to
reactions of the corresponding aryl bromides (entries 8, 9 and
18, 19). However, addition of water to the reaction of 4-
iodobenzotrifluoride led to a slightly higher ee than was
obtained with the aryl bromide under similar conditions
(entries 16 and 17).
Table 2: Scope of Pd-catalyzed asymmetric carboamination.[a]
The reactivity of substrates bearing disubstituted alkenes
was also briefly explored. The 2-methylallyl urea derivative 3
was converted to cyclic urea 4 in 72% yield and 76% ee
although a reaction temperature of 1358C was required to
effect complete conversion [Eq. (2)]. Addition of water or
TFA did not have a positive effect on either the chemical yield
or the enantioselectivity of this transformation. The 3-
phenylallyl urea substrate 5 was unreactive at 1358C, and
only trace amounts of product were obtained at 1608C
[Eq. (3)]. In order to determine the stereochemistry of the
1,2-addition reaction, Z-deuterioalkene substrate (Z)-[D]-1 f
was subjected to the optimized reaction conditions. This
transformation proceeded with syn-addition to the alkene to
afford [D]-2 f in 85% yield, 91% ee, and 7:1 d.r. [Eq. (4)].[12]
Entry
G
R-X
Additive[b] Product Yield ee
[%][c] [%]
1
2
3
4
5
6
7
8
9
NO2 p-CF3-C6H4-Br
NO2 p-CF3-C6H4-Br
NO2 m-CF3-C6H4-Br
NO2 o-CF3-C6H4-Br
NO2 p-PhC(O)-C6H4-Br
NO2 p-F-C6H4-Br
NO2 p-Cl-C6H4-Br
NO2 p-tBu-C6H4-Br
NO2 p-tBu-C6H4-I
NO2 Ph-Br
–
2g
2g
2h
2i
2j
2k
2l
2 f
2 f
2m
56
72
68
56
82
65
74
81
77
95
88
83
86
94
93
92
H2O
H2O
H2O
H2O
H2O
H2O
–
–
–
60[d] 47
10
83
71
89
89
11
NO2
–
2n
12
NO2
H2O
2o
80
87
13
14
NO2 p-MeO-C6H4-Br
NO2 m-MeO-C6H4-Br
TFA
–
2p
2q
80
75
90
83
15
CN
–
2r
65
86
16
17
18
19
20
CN p-CF3-C6H4-Br
CN p-CF3-C6H4-I
CN p-Me-C6H4-Br
CN p-Me-C6H4-I
CN p-MeO-C6H4-Br
H2O
H2O
–
–
–
2s
2s
2t
2t
2u
58
77
86
89
73
77
80
85
73
84
[a] Conditions: 1.0 equiv 1e or 1 f, 2.0 equiv ArX, 2.0 equiv NaOtBu,
2 mol% [Pd2(dba)3], 6 mol% (S)-Siphos-PE, xylenes (0.2m), 1158C
(substrate 1 f) or 1208C (substrate 1e), 14–18 h. [b] 2.0 Equiv water or
40 mol% TFA (trifluoroacetic acid) were added to the reaction mixture
prior to heating. [c] Yield of isolated products (average of two or more
runs). [d] This material contained ca. 35% of an unidentified regioiso-
mer.
encountered difficulty obtaining reproducible enantioselec-
tivities in reactions of electron-deficient aryl bromides with
1 f. After some exploration, we discovered that addition of
2.0 equiv of water to the reactions led to significantly
improved and reproducible enantioselectivities.[11] The cou-
pling of 2-bromonaphthalene or 3-bromoanisole with 1 f was
not significantly influenced by the addition of water
(entries 11 and 14). Addition of water had a negative
To illustrate the feasibility of deprotecting the N-aryl urea
products we examined removal of the p-nitrophenyl group
from 2m. In this representative case, cleavage of the N-aryl
substituent was cleanly accomplished using a three-step
procedure that required only a single chromatographic
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purification. As shown below, hydrogenation of 2m followed
by treatment with acetic anhydride and then oxidation with
ceric ammonium nitrate provided 6 in 88% overall yield
[Eq. (5)].
Several of the observations described above are quite
surprising, particularly when results obtained in the Pd/
Siphos-PE-catalyzed asymmetric carboaminations of ureas
are compared to those for related asymmetric Pd-catalyzed
carboamination reactions of N-Boc-pent-4-enylamines
(Scheme 1). For example, the [Pd2(dba)3]/(S)-Siphos-PE
Scheme 2. Mechanism of urea versus pyrrolidine formation.
yield 10 and 16,[16] which then undergo reductive elimination
to provide the observed major products 2 and 8.
The differences in absolute stereochemistry of products
obtained in reactions of the urea substrates versus the N-Boc
pentenylamine derivatives are likely due to a change in the
enantiodetermining step of the catalytic cycle. The product
stereocenter is generated during the migratory insertion step,
but two steps could potentially be enantiodetermining in this
catalytic cycle: 1) the migratory insertion step (e.g., 14b to
16); or 2) the subsequent reductive elimination step if
migratory insertion is reversible (e.g., 10 to 2).[16e] In our
prior studies[7a] we suggested that with the relatively electron-
rich N-boc pentenylamine substrate 7[17] the aminopalladation
is likely irreversible,[18] and relatively fast reductive elimina-
tion from 16[19] would provide the observed major pyrrolidine
stereoisomer 8 following enantiodetermining aminopallada-
tion (Scheme 2, bottom).
In contrast, the influence of N-aryl group electronic
properties and anionic ligands on enantioselectivity in
reactions of N-allyl ureas are consistent with a mechanism
for imidazolidin-2-one formation that proceeds through
reversible aminopalladation followed by enantiodetermining
reductive elimination (Scheme 2, top). Electron-withdrawing
N-substituents on the cyclizing nitrogen atom have been
Scheme 1. Stereochemistry of urea versus pyrrolidine formation.
catalyst provides (S)-imidazolidin-2-one products 2 in reac-
tions of 1e–f, whereas the same catalyst system afforded
pyrrolidine enantiomer 8 from 7.[13] Thus, despite the
similarities of the two substrates, the two reactions proceed
with the opposite absolute asymmetric induction. The positive
effect of water on asymmetric induction in Pd-catalyzed
reactions has rarely been observed,[14] and the water effect is
considerably different for the imidazolidin-2-one versus
pyrrolidine systems. Addition of water in reactions of 1e or
1 f with electron-deficient aryl bromides led to significantly
improved asymmetric induction. In contrast, addition of
water to reactions of N-Boc-pent-4-enylamine derivatives had
a highly deleterious effect, as no desired product was obtained
in these transformations.[15]
Despite the differences in the absolute product stereo-
chemistry in reactions of 1 versus 7, these transformations
appear to proceed through similar mechanisms and inter-
mediates. In both cases syn-1,2-addition to the alkene is
observed, and the ratio of ligand to Pd does not influence
asymmetric induction in either case.[7a] The mechanism of
both reactions proceeds through oxidative addition of the aryl
halide to Pd0 followed by substrate deprotonation and
substitution to provide alkene-bound palladium(aryl)(amido)
complexes 9a,b and 14a,b (Scheme 2).[6] These complexes
À
shown to decrease the rate of C C bond-forming reductive
elimination from complexes related to 10–11 and 15–16,[16a,c]
and to promote b-amidate elimination (retro-aminopallada-
tion) from these complexes.[16e] Thus, equilibration of
11Q9bQ9aQ10 is likely more facile for electron-poor
substrates 1e,f. Reductive elimination then occurs more
rapidly from 10 rather than 11 due to the chirality of the
ligand to yield the observed major enantiomer 2. In contrast,
equilibration (retro-aminopalladation) of 11 and 9b may
occur less readily for more electron-rich derivatives 1a–c,
À
undergo syn-1,2-migratory insertion into the Pd N bond to
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c) W. M. Kazmierski, E. Furfine, Y. Gray-Nunez, A. Spalten-
stein, L. Wright, Bioorg. Med. Chem. Lett. 2004, 14, 5685 – 5687.
[2] For other catalytic asymmetric syntheses of imidazolidin-2-ones,
see: a) H. Du, B. Zhao, W. Yuan, Y. Shi, Org. Lett. 2008, 10,
4231 – 4234; b) H. Du, B. Zhao, Y. Shi, J. Am. Chem. Soc. 2008,
130, 8590 – 8591; c) B. Zhao, H. Du, Y. Shi, J. Org. Chem. 2009,
74, 4411 – 4413; d) B. M. Trost, D. R. Fandrick, J. Am. Chem. Soc.
2003, 125, 11836 – 11837.
thus a greater amount of the minor enantiomer (i.e. lower
enantioselectivity) is obtained with these substrates due to an
inherent preference for insertion through 9b (as is the case for
14b in the N-Boc series).
The observed influence of anionic ligands[20] (iodide from
aryl iodides and hydroxide from added water) on these
transformations may be due to their effect on the rate of the
À
[3] G. Sartori, R. Maggi in Science of Synthesis (Houben-Weyl
Methods of Molecular Transformations) Vol. 18 (Eds.: S. V. Ley,
J. G. Knight), Thieme, Stuttgart, 2005, pp. 665 – 758.
[4] D. Lucet, T. L. Gall, C. Mioskowski, Angew. Chem. 1998, 110,
2724 – 2772; Angew. Chem. Int. Ed. 1998, 37, 2580 – 2627.
[5] For the synthesis of racemic ureas by Pd-catalyzed alkene
carboamination, see: a) J. A. Fritz, J. S. Nakhla, J. P. Wolfe, Org.
Lett. 2006, 8, 2531 – 2534; b) J. A. Fritz, J. P. Wolfe, Tetrahedron
2008, 64, 6838 – 6852.
[6] For recent reviews on Pd-catalyzed alkene carboamination
reactions, see: a) D. M. Schultz, J. P. Wolfe, Synthesis 2012,
351 – 361; b) J. P. Wolfe, Synlett 2008, 2913 – 2937.
[7] a) D. N. Mai, J. P. Wolfe, J. Am. Chem. Soc. 2010, 132, 12157 –
12159; b) T. W. Liwosz, S. R. Chemler, J. Am. Chem. Soc. 2012,
134, 2020 – 2023; c) W. Zeng, S. R. Chemler, J. Am. Chem. Soc.
2007, 129, 12948 – 12949; d) S. R. Chemler, Org. Biomol. Chem.
2009, 7, 3009 – 3019.
[8] X. X. Guo, J. H. Xie, G. H. Hou, W. J. Shi, L. X. Wang, Q. L.
Zhou, Tetrahedron: Asymmetry 2004, 15, 2231 – 2234.
[9] Use of (R)-Siphos-PE as the ligand led to formation of (R)-2b in
25% ee.
[10] Replacement of the substrate N-methyl group with other
substituents such as benzyl or p-methoxyphenyl did not lead to
improved enantioselectivities.
[11] A similar effect was observed when substoichiometric amounts
(50 mol%) of water or NaOH were added. However, the highest
degree of reproducibility was obtained with 2.0 equiv of added
water.
[12] The minor diastereomer likely arises through reversible b-
hydride elimination/reinsertion pathways. For further details,
see: M. B. Hay, J. P. Wolfe, J. Am. Chem. Soc. 2005, 127, 16468 –
16476. Additional details are also provided in the Supporting
Information.
C C bond-forming reductive elimination step, which could
perturb the equilibration between 11 and 9b.[21] Enantiose-
lectivities are improved for the combination of small hydrox-
ide ligand and electron-poor aryl halides, which is consistent
with the electron-rich hydroxide ligand slowing reductive
elimination (and thereby facilitating equilibration) for these
types of substrates that are otherwise prone to undergo
relatively rapid C C bond formation. This effect is mini-
[21]
À
mized for electron-neutral or -rich aryl halides where
reductive elimination is slow relative to electron-poor aryl
halides. In contrast, the relatively large iodide ligand may
increase the rate of reductive elimination through a steric
effect,[22] which is most pronounced with the electron-neutral
or -rich aryl halides. This would be expected to disfavor
equilibration of 11 and 9b and lead to diminished enantio-
selectivities as observed. The positive effect of trifluoroacetic
acid on the reaction of 4-bromoanisole with 1 f is also
presumably due to coordination of a trifluoroacetate anion to
10 and 11, although the precise nature of this effect is not
clear. The pronounced effect of anionic ligands on the
enantioselectivity of reactions of 1e,f likely does not arise
through anion binding to the metal prior to or during the
À
aminopalladation step. The insertion of alkenes into Pd N
bonds has previously been shown to proceed through 4-
coordinate alkene-bound complexes such as 9a,b or 14a,b,
and insertion from 5-coordinate species appears to be
unfavorable.[16]
In conclusion, we have developed a new catalytic asym-
metric synthesis of 4-benzyl-imidazolidin-2-one derivatives
through enantioselective carboamination reactions. The N-
allyl urea substrates are readily available (one step from
commercially available materials), and products are gener-
ated in good yield and up to 95% ee. Importantly, these
studies illustrate that the enantiodetermining step in asym-
metric Pd-catalyzed carboamination reactions may be influ-
enced by substrate structure, and that substrate electronics
and anionic additives also greatly affect levels of asymmetric
induction. These observations will likely be of significant
utility in the future development of other enantioselective
alkene difunctionalization reactions that involve potentially
reversible alkene insertion processes.
[13] D. N. Mai, Ph.D. Thesis, University of Michigan, Ann Arbor, MI,
2011.
[14] a) R. A. Fernandes, A. Stimac, Y. Yamamoto, J. Am. Chem. Soc.
2003, 125, 14133 – 14139; b) S. Rousseaux, J. Garcia-Fortanet,
M. A. Del Aguila Sanchez, S. L. Buchwald, J. Am. Chem. Soc.
2011, 133, 9282 – 9285.
[15] In contrast to asymmetric reactions of N-allyl ureas, trans-
formations of N-Boc-pent-4-enylamine derivatives proceed with
similar enantioselectivities for both aryl iodide and aryl bromide
substrates. See Ref. [7a].
[16] For studies on the mechanism of syn-migratory insertion of
À
alkenes into Pd N bonds, see: a) J. D. Neukom, N. S. Perch, J. P.
Wolfe, J. Am. Chem. Soc. 2010, 132, 6276 – 6277; b) P. S. Hanley,
D. Markovic, J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 6302 –
6303; c) J. D. Neukom, N. S. Perch, J. P. Wolfe, Organometallics
2011, 30, 1269 – 1277; d) P. S. Hanley, J. F. Hartwig, J. Am. Chem.
Soc. 2011, 133, 15661 – 15673; e) P. B. White, S. S. Stahl, J. Am.
Chem. Soc. 2011, 133, 18594 – 18597.
Received: July 3, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · asymmetric synthesis ·
[17] Our estimation of the relative electron-richness of the N-Boc
pentenylamine versus the p-nitrophenyl urea are based on
a comparison of pKa values for N1,N1-dimethyl-N2-(p-nitro-
phenyl)urea (pKa = 15.9, DMSO) versus N-Boc-benzylamine
(pKa = 22.9, DMSO); the stronger acid possesses a less electron-
rich nitrogen atom. See: a) J. P. Cheng, M. Xian, K. Wang, X.
Zhu, Z. Yin, P. G. Wang, J. Am. Chem. Soc. 1998, 120, 10266 –
10267; b) T. Mita, J. Chen, M. Sugawara, Y. Sato, Angew. Chem.
.
heterocycles · palladium · stereoselectivity
[1] a) J. Dumas, Curr. Opin. Drug Discovery Dev. 2002, 5, 718 – 727;
b) E. DeClercq, Biochem. Biophys. Acta. 2002, 1587, 258 – 275;
4
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2011, 123, 1429 – 1432; Angew. Chem. Int. Ed. 2011, 50, 1393 –
1396.
[20] a) For a review on the effects of anionic ligands in catalytic
asymmetric reactions, see: K. Fagnou, M. Lautens, Angew.
Chem. 2002, 114, 26 – 49; Angew. Chem. Int. Ed. 2002, 41, 26 – 47;
b) for a review on the effect of anionic ligands on Pd-catalyzed
asymmetric allylation reactions, see: B. M. Trost, T. Zhang, J. D.
Sieber, Chem. Sci. 2010, 1, 427 – 440.
[18] The syn-aminopalladation of N-aryl-pent-4-enylamines has been
shown to be irreversible in Pd/dppf complexes.[16c] Related
migratory insertions of ethylene into LPd-NPh2 complexes have
also been shown to be irreversible.[16b,d] The pKa of diphenyl-
amine (25.0) is comparable to that of N-Boc-benzylamine. See:
J. N. Li, L. Liu, Y. Fu, Q. X. Guo, Tetrahedron 2006, 62, 4453 –
4462.
À
[21] Small anionic ligands increase the rate of C C bond-forming
reductive elimination from five-coordinate L2Pd(Ar)(Ar1) com-
plexes. However, a small anionic ligand (ClÀ) has been shown to
À
[19] The observation that deuterated urea substrate (Z)-[D]-1 f is
converted to a 7:1 mixture of diastereomers whereas the
analogous deuterated carbamate is transformed with > 20:1
d.r. is consistent with relatively fast reductive elimination in the
carbamate system as compared to the urea. See: a) Ref. [12];
b) M. B. Bertrand, J. D. Neukom, J. P. Wolfe, J. Org. Chem. 2008,
73, 8851 – 8860.
dramatically decrease the rate of C C bond-forming reductive
elimination from four-coordinate anionic L1PdII(aryl)(alkyl)
complexes related to 10 and 11. See: a) B. Pudasaini, B. G.
Janesko, Organometallics 2011, 30, 4564 – 4571; b) C. Amatore,
A. Jutand, G. Le Duc, Chem. Eur. J. 2011, 17, 2492 – 2503.
[22] For a review, see: J. F. Hartwig, Inorg. Chem. 2007, 46, 1936 –
1947.
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Communications
Asymmetric Catalysis
B. A. Hopkins,
J. P. Wolfe*
&&&& — &&&&
Synthesis of Enantiomerically Enriched
Imidazolidin-2-Ones through
Asymmetric Palladium-Catalyzed Alkene
Carboamination Reactions
Positive water effect: A catalyst com-
posed of [Pd2(dba)3] (dba=dibenzylide-
neacetone) and (S)-Siphos-PE is effective
for the enantioselective coupling of N-
allyl ureas with aryl bromides to afford 4-
substituted imidazolidin-2-ones. Added
water leads to significantly improved
enantioselectivities with electron-poor
aryl halide substrates. It is suggested that
À
the C C bond-forming reductive elimi-
nation is the enantiodetermining step in
these reactions.
6
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