Palladium- or iridium-catalyzed allylic substitution of guanidines: Convenient and direct modification of guanidines

Article abstract of DOI:10.1021/jo802271d

(Chemical Equation Presented) As a convenient and direct functionalization of guanidines, the transition metal-catalyzed allylic substitution of guanidines was studied. The guanidine derivatives bearing two electron-withdrawing substituents acted as react

Full text of DOI:10.1021/jo802271d

Palladium- or Iridium-Catalyzed Allylic Substitution of Guanidines:
Convenient and Direct Modification of Guanidines
Hideto Miyabe,*,†,‡ Kazumasa Yoshida,† Valluru Krishna Reddy,† and Yoshiji Takemoto*,†
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan, and School of Pharmacy, Hyogo UniVersity of Health Sciences, Minatojima,
Chuo-ku, Kobe 650-8530, Japan
takemoto@pharm.kyoto-u.ac.jp; miyabe@huhs.ac.jp
ReceiVed October 10, 2008
As a convenient and direct functionalization of guanidines, the transition metal-catalyzed allylic substitution
of guanidines was studied. The guanidine derivatives bearing two electron-withdrawing substituents acted
as reactive nucleophiles in the allylic substitution to give the monoallylated products. The double allylic
substitution was achieved by using tri-Boc-guanidine bearing three electron-withdrawing substituents as
a nucleophile to give the diallylated products. The regiocontrol in the allylic substitution of unsymmetrical
allylic substrates has been investigated by employing the palladium or iridium catalysts. The iridium
complex of chiral pybox ligand allowed the regio- and enantioselective allylic substitution. Asymmetric
double allylic substitution of tri-Boc-guanidine with phosphate bearing the 1-naphthyl group gave the
diallylated product with high diastereo-, regio-, and enantioselectivities.
Introduction
In contrast to the numerous studies on constructing the
guanidine structures,5–11 the direct modification of guanidines
has received much less attention. Until recently, there have been
only two methods those are commonly used for the function-
Guanidine functionality is found in many biologically active
natural products and pharmaceutically relevant compounds, and
it plays a key role in their activities.1,2 In addition to pharma-
ceutical roles, the guanidines have been recently utilized in
organic synthesis as general strong bases and organocatalysts.3
The utility of guanidine-derived ionic liquids was also shown
in organic synthesis.4 Hence, a significant number of methods
andreagentsforpreparationofguanidineshavebeendeveloped.5-9
Traditionally, guanidines are prepared by the reaction of amines
with cyanamides or S-alkylisothiouronium salts;10 thus, the
synthetic studies of guanidines have mainly focused on the
development of efficient guanylating-agents of amine and
diamine precursors.11
(3) For examples of strong bases or organocatalysts containing guanidine
functionality, see: (a) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
9228. (b) Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-T. Angew. Chem.,
Int. Ed. 2008, 47, 5641. (c) Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.;
Nakanishi, W.; Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008,
73, 133. (d) Takada, K.; Takemura, N.; Cho, K.; Sohtome, Y.; Nagasawa, K.
Tetrahedron Lett. 2008, 49, 1623. (e) Terada, M.; Ikehara, T.; Ube, H. J. Am.
Chem. Soc. 2007, 129, 14112. (f) Fu, X.; Jiang, Z.; Tan, C.-T. Chem. Commun.
2007, 5058. (g) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh,
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M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. (i) Shen, J.; Nguyen, T. T.;
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Fukuda, K.; Ishikawa, T. AdV. Synth. Catal. 2005, 347, 1653. (m) Sohtome, Y.;
Hashimoto, Y.; Nagasawa, K. AdV. Synth. Catal. 2005, 347, 1643. (n) Allingham,
M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. W. R.
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2002, 8, 552. (p) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.;
Isobe, T. Chem. Commun. 2001, 245. (q) Isobe, T.; Fukuda, K.; Araki, Y.;
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† Kyoto University.
‡ Hyogo University of Health Sciences.
(1) (a) Berlinck, R. G. S. Fortschr. Chem. Org. Naturst. 1995, 66, 119. (b)
Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339.
(2) For reviews on guanidine-containing natural products, see: (a) Aron, Z. D.;
Overman, L. E. Chem. Commun. 2004, 253. (b) Heys, L.; Moore, C. G.; Murphy,
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10.1021/jo802271d CCC: $40.75
Published on Web 11/16/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 305–311 305

Miyabe et al.
alization of guanidines. The first method involves the reaction
of guanidine with alcohols under Mitsunobu reaction condi-
tions.12 The second method is the alkylation of guanidine with
electrophiles such as alkyl halides under basic conditions.13
Recently, several new methods for the modification of guanidines
have been reported.14,15 However, the transition metal-catalyzed
modification of guanidines has not been widely studied,16
probable due to their strong basic character and high metal-
coodination ability.17 We focused our attention on the transition
metal-catalyzed allylic substitution of guanidines from the point
of view of synthetic application. Our recent studies show that
the nitrogen atom of guanidine derivatives having two N-
electron-withdrawing substituents acted as a reactive nucleophile
in the allylic substitution.18,19 In this paper, we describe full
details of a convenient and direct modification of guanidines
based on palladium- or iridium-catalyzed allylic substitution to
address the functionalized guanidines. As shown below, this
reaction is extremely facile and gives the allylated guanidines
in good yields under mild reaction conditions. Regio- and
enantioselective allylic substitution was also achieved by using
the iridium complex of the chiral pybox ligand.
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Results and Discussion
Palladium-Catalyzed Allylic Substitution of Guanidines. The
utility of guanidines in allylic substitution has not been
investigated, though guanidines are attractive reagents for the
synthesis of functionalized allylic compounds. Our methodology
utilizes guanidines as a nucleophile in the transition metal-
catalyzed allylic substitution. Significant advances were achieved
with the introduction of electron-withdrawing substituents on
nitrogen atoms of guanidine that allowed for the direct synthesis
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306 J. Org. Chem. Vol. 74, No. 1, 2009

Pd- or Ir-Catalyzed Allylic Substitution of Guanidines
SCHEME 2. Palladium-Catalyzed Allylic Substitution of
Guanidine Derivatives
FIGURE 1. Guanidines 1-3 having electron-withdrawing substituents.
SCHEME 1. Palladium-Catalyzed Allylic Substitution of
Guanidine 2A
TABLE 1. The Palladium-Catalyzed Allylic Substitution of
Guanidines 1-2Ba
of protected guanidines. We recently observed that hydroxy-
lamines having an N-electron-withdrawing substituent acted as
a reactive nucleophile in allylic substitution.20a A similar trend
was observed in our recent studies on O-allylic substitution of
oximes.20b,c On the basis of these results, we suggest that
electron-withdrawing substituents would be important for the
nucleophilic property of guanidines. Therefore, the substrates
of choice were guanidines 1-3 bearing electron-withdrawing
substituents (Figure 1). Additionally, the advantage of N-
protected guanidines is that the purification of products by
chromatography has been facile due to their less polar nature.
The viability of guanidines in the palladium-catalyzed reaction
is the first focus of our effort.21 The reaction of guanidines 1
and 2A with allylic carbonate 4a was investigated in the
presence of Pd(PPh3)4. However, mono-Boc-guanidine 122 did
not exhibit a good reactivity toward the π-allyl palladium
complex.18 In contrast, guanidine 2A bearing two Boc groups
has shown excellent reactivity (Scheme 1). In the presence of
Pd(PPh3)4 (8 mol %), the reaction of guanidine 2A with allylic
carbonate 4a (2.2 equiv) was run in CH2Cl2 at 20 °C for 2 h.
1H NMR measurement of the crude product showed almost
quantitative conversion of 2A to the monoallylated product 5Aa
with excellent selectivity. The product 5Aa was obtained in 82%
yield after purification by preparative TLC. The structure of
5Aa was confirmed by the comparison of spectra of authentic
allylated guanidine.13a The allylation took place selectively at
the nitrogen atom bearing the Boc group. It is also noteworthy
that the formation of diallylated product was not observed under
the reaction conditions.
entry
guanidine
reagent
time (h)
product
yield (%)
1
2
3
4
5
1
4b
4b
6b
4b
6b
24
2
24
2
NR
86
NR
88
2A
2A
2B
2B
5Ab
5Bb
24
NR
a Reactions were carried out with guanidine 1-2B and reagent 4b or
6b (2.2 equiv) in the presence of Pd(PPh3)4 (8 mol%) in CH2Cl2 at 20
°C.
6b having a phenyl group in CH2Cl2 (Scheme 2). In the case of
the reaction of mono-Boc-guanidine 1 with allylic carbonate
4b, no reaction occurred after 24 h of stirring at 20 °C (Table
1, entry 1). In contrast to 1, the di-Boc-guanidine 2A worked
well as a nucleophile. In the presence of Pd(PPh3)4 (8 mol %),
a reaction of guanidine 2A with allylic carbonate 4b (2.2 equiv)
gave the linear product 5Ab in 86% yield, after 2 h of stirring
(entry 2). These observations suggest that the stability of
conjugate base A of guanidine would be of key importance in
the present reaction. Thus, a rational hypothesis of this reaction
is that guanidine 2A would be effectively deprotonated by
methoxide generated from carbonate 4b. The solvent influenced
the reactivity of guanidines. In regard to the solvent effect, the
replacement of CH2Cl2 with MeCN also gave a good result,
while nonpolar solvents such as toluene gave a poor yield of
product 5Ab. The allylic substitution with acetate 6b did not
take place (entry 3). The observed beneficial effect of carbonate
4b over acetate 6b is noteworthy. This observation suggests
that acetate anion, generated from palladium and acetate 6b, is
less effective for activation of guanidine 2A as a base. Although
the effect of bases on the reaction of guanidine 2A with acetate
6b was investigated by employing K2CO3, Et2Zn, and KOH,
only low yields of product 5Ab were observed due to the
formation of insoluble complex from guanidine 2A and bases.
Thus, the combination of allylic carbonates and guanidines
having two electron-withdrawing substituents is a highly
promising approach to the direct functionalization of guanidines.
We next investigated the reaction of di-Cbz-guanidine 2B
(entries 4 and 5). As expected, the di-Cbz-guanidine 2B worked
well and a similar trend was observed. The selective formation
of monoallylated product 5Bb was observed in the reaction with
carbonate 4b (entry 4), although the acetate 6b was less effective
(entry 5).
We next investigated the palladium-catalyzed reaction of
guanidines 1-2B with allylic carbonate 4b and allylic acetate
(20) For the allylic substitution with hydroxylamines having an N-electron-
withdrawing substituent or oximes; see: (a) Miyabe, H.; Yoshida, K.; Matsumura,
A.; Yamauchi, M.; Takemoto, Y. Synlett 2003, 567. (b) Miyabe, H.; Matsumura,
A.; Yoshida, K.; Yamauchi, M.; Takemoto, Y. Synlett 2004, 2123. (c) Miyabe,
H.; Yoshida, K.; Reddy, V. K.; Matsumura, A.; Takemoto, Y. J. Org. Chem.
2005, 70, 5630.
(21) For reviews on allylic substitution, see: (a) Frost, C. G.; Howarth, J.;
Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (b) Trost, B. M.;
Van Vranken, D. L. Chem. ReV. 1996, 96, 395. (c) Johannsen, M.; Jorgensen,
K. A. Chem. ReV. 1998, 98, 1689. (d) Pfaltz, A.; Lautens, M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, Germany, 1999; Vol. 2, pp 833-884. (e) Helmchen, G. J. Organomet.
Chem. 1999, 576, 203. (f) Trost, B. M.; Lee, C. B. In Catalytic Asymmetric
Synthesis II; Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000; pp 593-
650. (g) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (h) Trost, B. M.; Crawley,
M. L. Chem. ReV. 2003, 103, 2921. (i) Graening, T.; Schmalz, H.-G. Angew.
Chem., Int. Ed. 2003, 42, 2580. (j) Trost, B. J. Org. Chem. 2004, 69, 5813. (k)
Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
Iridium-Catalyzed Allylic Substitution of Guanidines. The
regiocontrol has been of great importance in allylic substitu-
tion.23 Recently, the iridium-catalyzed regioselective allylic
(22) Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett.
2001, 3, 1133.
J. Org. Chem. Vol. 74, No. 1, 2009 307

Miyabe et al.
SCHEME 4. Reaction of Unsymmetrical Guanidine
SCHEME 3. Iridium-Catalyzed Allylic Substitution of
Guanidine Derivatives
TABLE 2. The Iridium-Catalyzed Allylic Substitution of
Guanidines 1-2Ba
entry guanidine reagent solvent time (h) product yield (%)
1
2
3
4
5
6
1
4b
4b
4b
6b
4b
6b
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
24
3
2
24
2
24
NR
63
88
NR
87
NR
2A
2A
2A
2B
2B
7Ab
7Ab
7Bb
a Reactions were carried out with guanidine 1-2B and reagent 4b or
6b (2.2 equiv) in the presence of [IrCl(cod)]2 (4 mol %) at 20 °C.
63% yield without the formation of the linear product 5Ab. The
formation of diallylated products was not observed in the
iridium-catalyzed reaction as well as the palladium-catalyzed
reaction. The reaction proceeded effectively in CH3CN to give
the branched product 7Ab in 88% yield, after being stirred for
2 h (entry 3). The use of toluene as solvent led to a prolonged
reaction time. The reaction of di-Cbz-guanidine 2B with
carbonate 4b afforded a good yield of the branched product
7Bb with excellent regioselectivities (entry 5). The scope of
suitable electrophiles was limited to carbonates; thus, acetate
6b did not work (entries 4 and 6).
For the further modification of guanidines, the reaction of
unsymmetrical guanidine 2D bearing different electron-with-
drawing substituents was tested. Guanidine 2D was prepared
from mono-Boc-guanidine 1 (Scheme 4). At first, we investi-
gated the palladium-catalyzed reaction of guanidine 2D with
carbonate 4b in CH2Cl2. Although the reaction of 2D proceeded
smoothly to give a 3:1 mixture of allylated products 8 and 9 in
88% combined yield, these isomers 8 and 9 could not be
separated by preparative TLC or flash column chromatography.
In contrast, the iridium-catalyzed reaction of 2D with carbonate
4b in MeCN gave the branched products 10 and 11. These
isomers could be easily separated by preparative TLC and the
products 10 and 11 were obtained in 62% and 31% yields,
respectively. Next, the further allylation of allylated product 10
was examined. However, allylation of 10 did not proceed even
under the basic reaction conditions with allyl halides. The further
allylation was achieved after the deprotection of the Boc group
on 10. Treatment of 10 with trifluoroacetic acid in CH2Cl2 gave
the deprotected product 12 in 82% yield. The allylation of 12
under the basic reaction conditions with allyl bromide gave the
diallylated product 13 in 53% yield.
Double Allylic Substitution of Guanidines. As mentioned
above, the diallylation is a challenging task; thus, the double
allylic substitution of guanidines is the next focus of our effort.
To test the reactivity of guanidines toward the π-allyl complex,
we reexamined the palladium-catalyzed reaction by employing
guanidines 2A-C and 3 (Scheme 5). In the presence of
Pd(PPh3)4, the reaction of di-Boc-guanidine 2A, di-Cbz-guani-
dine 2B, and di-Bz-guanidine 2C bearing two electron-
withdrawing substituents gave the monoallylated products
5Ab-5Cb even under reflux (Table 3, entries 1-3). The double
allylic substitution was achieved by using tri-Boc-guanidine 3
as a nucleophile. The palladium-catalyzed reaction of tri-Boc-
guanidine 3 with allylic carbonate 4b (4 equiv) gave the
amination of unsymmetrical acyclic substrates giving the
branched products was studied by Takeuchi’s group.24 There-
fore, the iridium-catalyzed allylic substitution has been a subject
of current interest.23,25 Recently, important contributions in this
area come from Helmchen and Hartwig.26,27
For the selective preparation of the branched products, the
iridium-catalyzed reaction was investigated (Scheme 3). Al-
though the mono-Boc-guanidine 1 did not work (Table 2, entry
1), the guanidines 2A and 2B bearing two electron-withdrawing
substituents have shown a good reactivity. The reaction of di-
Boc-guanidine 2A with allylic carbonate 4b (2.2 equiv) was
run in CH2Cl2 in the presence of [IrCl(cod)]2 (4 mol %) at 20
°C (entry 2). As expected, the reaction proceeded smoothly with
excellent regioselectivity to give the branched product 7Ab in
(23) For reviews, see: (a) Takemoto, Y.; Miyabe, H. In ComprehensiVe
Organometallic Chemistry, 3rd ed. (COMC-III); Crabtree, R. H., Mingos,
D. M. P., Eds.; Elsevier: Oxford, UK, 2006; Vol. 10.15, pp 695-724. (b) Lee,
C.; Matunas, R. In ComprehensiVe Organometallic Chemistry, 3rd ed. (COMC-
III); Crabtree, R. H., Mingos, D. M. P., Eds.; Elsevier: Oxford, UK, 2006; Vol.
10.14, pp 649-693.
(24) For some selected examples, see: (a) Kezuka, S.; Kanemoto, K.;
Takeuchi, R. Tetrahedron Lett. 2004, 45, 6403. (b) Takeuchi, R.; Ue, N.; Tanabe,
K.; Yamashita, K.; Shiga, N. J. Am. Chem. Soc. 2001, 123, 9525. (c) Takeuchi,
R.; Ue, N.; Tanabe, K. Angew. Chem., Int. Ed. 2000, 39, 1975. (d) Takeuchi,
R.; Shiga, N. Org. Lett. 1999, 1, 265. (e) Takeuchi, R.; Kashio, M. J. Am. Chem.
Soc. 1998, 120, 8647. (f) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. 1997,
36, 263. For a review, see: (g) Takeuchi, R. Synlett 2002, 1954.
(25) For reviews on the iridium-catalyzed allylic substitution, see: (a)
Helmchen, G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.; Weihofen, R. Chem.
Commun. 2007, 675. (b) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349.
(26) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. (b)
Lo´pez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 3426. (c)
Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2003,
125, 14272. (d) Shu, C.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4794.
(e) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4797.
(f) Leitner, A.; Shu, C.; Hartwig, J. F. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5830. (g) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 15506. (h) Leitner, A.; Shu, C.; Hartwig, J. F. Org. Lett. 2005,
7, 1093. (i) Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 11770. (j) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F.
J. Am. Chem. Soc. 2007, 129, 7508. (k) Pouy, M. J.; Leitner, A.; Weix, D. J.;
Ueno, S.; Hartwig, J. F. Org. Lett. 2007, 9, 3949. (l) Markovic´, D.; Hartwig,
J. F. J. Am. Chem. Soc. 2007, 129, 11680. (m) Ueno, S.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2008, 47, 1928.
(27) (a) Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 116. (b) Welter,
C.; Koch, O.; Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896. (c)
Weihofen, R.; Dahnz, A.; Brunner, B.; Streiff, S.; Duebon, P.; Helmchen, G.
Org. Lett. 2005, 7, 1239. (d) Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen,
G. Chem. Commun. 2005, 3541. (e) Welter, C.; Moreno, R. M.; Streiff, S.;
Helmchen, G. Org. Biomol. Chem. 2005, 3, 3266. (f) Weihofen, R.; Tverskoy,
O.; Helmchen, G. Angew. Chem., Int. Ed. 2006, 45, 5546.
308 J. Org. Chem. Vol. 74, No. 1, 2009

Pd- or Ir-Catalyzed Allylic Substitution of Guanidines
SCHEME 5. Double Allylic Substitution of Guanidine
SCHEME 7. Enantioselective Allylic Substitution of
Guanidines
TABLE 3. The Double Allylic Substitution of Guanidines 2A-3
T
yield
entry guanidine reagent
catalyst
(°C) time (h) product (%)
ing work has been done by using chiral ferrocenylphosphine-
palladium complexes by Hayashi and Ito.28 The regio- and
stereoselectivities of allylic substitution with iridium catalyst
arequitedifferentfromthoseofpalladium-catalyzedamination.23,25,29
In recent years, the control of regio- and enantioselectivities in
iridium-catalyzed allylic amination and etherification has been
mainly studied by Hartwig26 and Helmchen,27 respectively.
Hence, the regio- and enantioselective allylic substitution with
chiral iridium complex has been a subject of current interest.30-33
Recently, we reported that the iridium complex of pybox
ligand catalyzed the allylic substitution to form the branched
product with good enantioselectivity.34 Therefore, the utility of
the iridium-pybox complex in reaction of guanidines has been
the new focus of our efforts.35,36 At first, we investigated the
monoallylation reaction of guanidines 2A-C having two
electron-withdrawing substituents with phosphates 19b and 19b
(Scheme 7). As expected, the chiral iridium complex of the
pybox ligand exhibited a good activity under basic reaction
conditions, although the reaction of phosphates did not proceed
effectively in the absence of the base. The reaction of di-Boc-
1a
2a
3a
4a
5a
6b
2A
2B
2C
3
3
3
4b
4b
4b
4b
4a
4b
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
reflux
reflux
reflux
20
2
2
2
1
1
1
5Ab
5Bb
5Cb
14b
14a
15b
90
86
89
94
99
85
20
[IrCl(cod)]2 20
a Reactions were carried out with guanidine 2A-3 and reagent 4a,b
(4 equiv) in CH2Cl2 in the presence of Pd(PPh3)4 (8 mol %). b Reaction
was carried out with guanidine 3 and reagent 4b (4 equiv) in CH3CN in
the presence of [IrCl(cod)]2 (4 mol %).
SCHEME 6. Sequential Allylic Substitution of Guanidine
(28) Hayashi, T.; Kishi, K.; Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990,
31, 1743.
(29) For our studies on the iridium-catalyzed reaction, see: (a) Kanayama,
T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003, 42,
2054. (b) Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, Y.; Takemoto, Y.
J. Org. Chem. 2003, 68, 6197. (c) Miyabe, H.; Yoshida, K.; Kobayashi, Y.;
Matsumura, A.; Takemoto, Y. Synlett 2003, 1031. (d) Miyabe, H.; Takemoto,
Y. Synlett 2005, 1641.
(30) (a) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem., Int. Ed.
2004, 43, 2426. (b) Polet, D.; Alexakis, A. Org. Lett. 2005, 7, 1621. (c) Polet,
D.; Alexakis, A.; Tissot-Croset, K.; Corminboeuf, C.; Ditrich, K. Chem. Eur. J.
2006, 12, 3596.
(31) (a) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem.
Soc. 2004, 126, 1628. (b) Lyothier, I.; Defieber, C.; Carreira, E. M. Angew.
Chem., Int. Ed. 2006, 45, 6204. (c) Defieber, C.; Ariger, M. A.; Moriel, P.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139.
(32) Kimura, M.; Uozumi, Y. J. Org. Chem. 2007, 72, 707.
(33) (a) Singh, O. V.; Han, H. J. Am. Chem. Soc. 2007, 129, 774. (b) Singh,
O. V.; Han, H. Org. Lett. 2007, 9, 4801. (c) Singh, O. V.; Han, H. Tetrahedron
Lett. 2007, 48, 7094.
(34) For our studies on asymmetric iridium-catalyzed allylic substitution with
heteroatom nucleophiles, see: (a) Miyabe, H.; Matsumura, A.; Moriyama, K.;
Takemoto, Y. Org. Lett. 2004, 6, 4631. (b) Miyabe, H.; Yoshida, K.; Yamauchi,
M.; Takemoto, Y. J. Org. Chem. 2005, 70, 2148. (c) Reddy, V. K.; Miyabe, H.;
Yamauchi, M.; Takemoto, Y. Tetrahedron 2008, 64, 1040.
(35) The utility of the C2-symmetric pybox ligand in transition metal-catalyzed
allylic substitution has not been wildly invesitigated. See: (a) Bourguignon, J.;
Bremberg, U.; Dupas, G.; Hallman, K.; Hagberg, L.; Hortala, L.; Levacher, V.;
Lutsenko, S.; Macedo, E.; Moberg, C.; Que´guiner, C.; Rahm, F. Tetrahedron
2003, 59, 9583. (b) Chelucci, G.; Deriu, S.; Pinna, G. A.; Saba, A.; Valenti, R.
Tetrahedron: Asymmetry 1999, 10, 3803.
diallylated product 14b in 94% yield (entry 4). Good chemical
yield was also observed in the reaction of tri-Boc-guanidine 3
with carbonate 4a (entry 5). The iridium-catalyzed reaction of
3 with 4b proceeded smoothly to give the branched and
diallylated adduct 15b in 85% yield.
The diallylation reaction could be extended to the sequential
reaction (Scheme 6). The tri-Boc-guanidine 16, prepared from
the allylated di-Boc-guanidine 7Ab, was used as a precursor
for second allylic substitution. As expected, tri-Boc-guanidine
16 displayed an excellent reactivity in the palladium-catalyzed
reaction to give the diallylated product 17 in 91% yields. Cyclic
guanidine 18 was obtained by the RCM reaction of 17, using
Grubbs’ second generation catalyst.
Regio- and Enantioselective Allylic Substitution of
Guanidines. Asymmetric allylic substitutions have been de-
veloped as fundamentally important reactions.21,23 The allylic
amination of 1,3-symmetrical substrates has been widely studied
including enantioselective versions. On the other hand, the allylic
amination of unsymmetrical substrates is challenging, since both
regio- and enantioselectivities should be controlled to give the
desired branched products with high enantiopurity. The pioneer-
(36) The iridium-idane-pybox catalyst was used in the reductive aldol
reaction. See: Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org.
Lett. 2001, 3, 1829.
J. Org. Chem. Vol. 74, No. 1, 2009 309

Miyabe et al.
TABLE 4. The Enantioselective Allylic Substitution of Guanidines
SCHEME 8. Enantioselective Double Allylic Substitution of
Guanidine
2A-2Ca
T
time yield
product
(ratioc)
ee
entry guanidine reagent (°C) (h) (%)b
(%)d
1
2
3
4
5
6
2A
2A
2B
2B
2C
2A
19b
19b
19b
19b
19b
19c
-20
-30
-20
-30
3
3
3
3
83 7Ab:5Ab (75:25) 90
81 7Ab:5Ab (76:24) 96
74 7Bb:5Bb (60:40)
70 7Bb:5Bb (66:34)
87
87
-20 50
63 7Cb:5Cb (25:75) 34
69 7Ac:5Ac (>95:5) 96
-20
8
a Reactions were carried out with guanidine 2A-C and reagent 19b,c
(1.5 equiv) in the presence of [IrCl(cod)]2 (8 mol %) and pybox 20 (16
mol %). b Combined yield of 7Ab-Cb and 5Ab-Cb. c Ratio for
7Ab-Cb:5Ab-Cb. d Enantioselectivity was determined by HPLC
analysis.
TABLE 5. The Enantioselective Double Allylic Substitution of
Guanidine 3a
ee (%)d
T
time yield
entry reagent (°C) (h) (%)
ratiob
20 10 88e 4:81:15
drc
15b,c 21b
1
2
3
4
19b
19b
19c
19c
25:75
74:26
90:10
64
–20 20 90e 58:30:12
99
99
99
88
20 10 77f
–20 20 81f
97:3:trace
100:trace:trace 97:3
a Reactions were carried out with guanidine 3 and reagent 19b,c (2.5
equiv) in the presence of [IrCl(cod)]2 (8 mol %) and pybox 20 (16 mol
%). b Ratio for 15b,c:21b,c:14b,c. c Dr for dl-15b,c:meso-15b,c.
d Enantioselectivity was determined by HPLC analysis. e Combined
yield of products. f Yield of dl-15c.
Finally, we studied the viability of the iridium complex of
the pybox ligand in the double allylic substitution of tri-Boc-
guanidine 3 (Scheme 8). The double allylic substitution is
challenging, because chiral iridium complex should control the
diastereoselectivity as well as regioselectivity and enantiose-
lectivity. At first, the reaction of tri-Boc-guanidine 3 with allylic
phosphate 19b was carried out in CH2Cl2 at 20 °C under basic
reaction conditions (Table 5, entry 1). However, the mixture of
products 15b, 21b, and 14b was obtained in 88% combined
yield in a 4:81:15 ratio. The chemical yield for product 15b
was shown to be dependent on the reaction temperature, thus
changing the temperature from 20 to -20 °C led to an effective
increase in the yield of the desired compound 15b (entry 2).
The moderate diasteroselectivity was observed to give the
diastereomers dl-15b and meso-15b in a 74:26 ratio, ac-
companied by the product 21b with 88% ee. Enantiomeric
excess of major diastereomer dl-15b was determined to be
>99% ee by high-performance liquid chromatography analysis.
The enhanced enantioselectivity of dl-15b can be explained by
kinetic resolution during the second allylation step of monoal-
lylated product. The ratio of undesired products to desired
products was also dependent on the structure of allylic phos-
phates (entries 3 and 4). When phosphate 19c having a
1-naphthyl group was employed, high diastere-, regio-, and
enantioselectivities were observed. The reaction conducted at
-20 °C gave the desired product dl-15c in 81% yield with
>99% ee (entry 4).
FIGURE 2. Model to explain enantioselectivity.
guanidine 2A with 19b proceeded smoothly to give good yields
of products 7Ab and 5Ab, although a low regioselectivity was
observed (Table 4, entry 1). Enantiomeric excess of 7Ab was
determined to be 90% ee by high-performance liquid chroma-
tography analysis. The absolute configuration of product 7Ab
was assumed from the similarity between the present reaction
and our previously reported reaction.34 The reaction of 2A with
19b at -30 °C gave 96% ee of branched product 7Ab with a
76:24 regioselectivity (entry 2). The replacement of di-Boc-
guanidine 2A with di-Cbz-guanidine 2B or di-Bz-guanidine 2C
led to a decrease in the enantioselectivity and regioselectivity
(entries 3-5). The use of phosphate 19c having a 1-naphthyl
group led to an increase in regioselectivity to >95:5 and
enantioselectivity to 96% ee (entry 6).
Recently, Gamasa reported the structure of the π-allyl iridium
complex with the pybox ligand having isopropyl groups B
(Figure 2).37 The stereochemistry of complex B has been
confirmed by a single-crystal X-ray analysis. The X-ray crystal
structure determination shows a pseudooctahedral geometry
around the iridium atom, which is bonded to the chloride atom
and to the three nitrogen atoms of the pybox ligand. The π-allyl
fragment formally occupied two coordination sites. On the basis
of Gamasa’s study, the stereochemical feature of our reaction
can be rationalized in terms of steric control in the π-allyl
iridium complex. The complex C would be preferred over
complex D due to repulsion between two phenyl groups of the
allyl fragment and the pybox ligand as shown in D.
Conclusion
We have demonstrated that the nitrogen atoms of guanidines
bearing electron-withdrawing substituents act as reactive nu-
cleophiles in the palladium- or iridium-catalyzed allylic substitu-
tion These reactions provided a new method for direct func-
(37) For iridium pybox complexes, see: (a) Diez, J.; Gamasa, M. P.; Gimeno,
J.; Paredes, P. Organometallics 2005, 24, 1799. (b) Paredes, P.; D´ıez, J.; Gamasa,
M. P. Organometallics 2008, 27, 2597.
310 J. Org. Chem. Vol. 74, No. 1, 2009

Pd- or Ir-Catalyzed Allylic Substitution of Guanidines
425 (M+, 9), 167 (100). HRMS (FAB+) calcd for C24H31N3O4 (M+)
425.2315, found 425.2324. Anal. Calcd for C24H31N3O4: C, 67.74;
H, 7.34; N, 9.88. Found: C, 67.69; H, 7.27; N, 9.84. HPLC
(Chiralcel AD-H, hexane/2-propanol ) 95/5, 0.5 mL/min, 254 nm)
tr(S) ) 10.5 min, tr(R) ) 9.5 min. A sample of 96% ee (S) by
tionalization of protected guanidine derivatives. In addition to
the enantioselective monoallylation, the enantioselective double
allylic substitution of tri-Boc-guanidine disclosed a broader
aspect of the utility of the iridium-pybox complex in allylic
substitutions.
HPLC analysis gave [R]20 -185.2 (c 1.4, CHCl3).
D
N1,N2-Bis(benzyloxycarbonyl)-N1-(1-phenyl-2-propenyl)guani-
dine (7Bb). A white solid. IR (CHCl3) 3389, 1717, 1612 cm-1. 1H
NMR (CDCl3) δ 9.61 (1H, br s), 9.36 (1H, br s), 7.41-7.10 (14H,
m), 6.82 (2H, d, J ) 7.0 Hz), 6.28 (1H, m), 5.39 (1H, d, J ) 17.1
Hz), 5.33 (1H, d, J ) 10.3 Hz), 5.14, 5.13 (2H, AB q, J ) 13.4
Hz), 4.96, 4.93 (2H, AB q, J ) 12.2 Hz); 13C NMR (CDCl3) δ
163.9, 161.1, 155.7, 140.5, 136.9, 134.7, 134.0, 128.4 (2C), 128.3,
128.2, 128.0, 127.8, 126.6, 125.9, 120.3, 68.7, 67.1, 58.9; one
carbon peak was missing due to overlapping. MS (EI+) m/z 433
(M+, 24), 91 (100). HRMS (EI+) calcd for C26H25N3O4 (M+)
443.1845, found 443.1850. HPLC (Chiralcel AD-H, hexane/2-
propanol ) 90/10, 0.5 mL/min, 254 nm) tr(S) ) 27.6 min, tr(R) )
Experimental Section
General Procedure for Enantioselective Iridium-Catalyzed
Monoallylation. A mixture of guanidine 2A-C (0.15 mmol) and
CsOH·H2O (27 mg, 0.15 mmol) in CH2Cl2 (1.0 mL) was stirred
under argon atmosphere at 20 °C for 10 min. To the reaction
mixture was added a solution of allylic phosphate 19b,c (0.23
mmol), pybox 20 (9.1 mg, 0.025 mmol), and [IrCl(cod)]2 (8.3 mg,
0.012 mmol) in CH2Cl2 (0.5 mL) at -20 or -30 °C. After the
reaction was completed, the reaction mixture was diluted with
saturated NH4Cl and then extracted with CH2Cl2. The organic phase
was dried over MgSO4 and concentrated at reduced pressure. The
17.6 min. A sample of 87% ee (S) by HPLC analysis gave [R]29
D
1
ratio of products was determined by H NMR analysis of crude
-44.8 (c 1.04, CHCl3).
N1,N2-Bis(phenylcarbonyl)-N1-(1-phenyl-2-propenyl)guanidine (7Cb).
A white solid. IR (CHCl3) 3283, 1675, 1616 cm-1.1H NMR (CDCl3)
δ 10.02 (1H, d, J ) 7.0 Hz), 8.24 (2H, d, J ) 6.7 Hz), 8.06 (2H,
d, J ) 7.3 Hz), 7.65-7.30 (12H, m), 6.20-6.13 (2H, m), 5.39
(1H, d, J ) 15.6 Hz), 5.34 (1H, d, J ) 9.2 Hz); 13C NMR (CDCl3)
δ 178.9, 168.6, 156.2, 140.1, 137.7, 137.0, 133.6, 132.0 (2C), 129.6,
129.2, 128.9, 128.0 (2C), 127.9, 127.2, 116.4, 57.1; MS (FAB+)
m/z 384 (M + H+, 71), 154 (100). HRMS (FAB+) calcd for
C24H22N3O2 (M + H+) 384.1712, found 384.1703. HPLC (Chiralcel
AD-H, hexane/2-propanol ) 90/10, 0.5 mL/min, 254 nm) tr(S) )
20.5 min, tr(R) ) 15.6 min. A sample of 34% ee (S) by HPLC
products. Purification of the residue by preparative TLC (hexane:
AcOEt ) 10:1, 2-fold development) afforded the products
7Ab-7Cb and 5Ab-5Cb.
N1,N2-Bis(tert-butyloxycarbonyl)-N1-(1-phenyl-2-propenyl)guani-
dine (7Ab). A white solid. IR (CHCl3) 3384, 1711, 1609 cm-1. 1H
NMR (CDCl3) δ 9.49 (1H, br s), 9.31 (1H, br s), 7.31-7.24 (2H,
m), 7.22-7.15 (4H, m), 6.33 (1H, m), 5.49 (1H, d, J ) 17.1 Hz),
5.41 (1H, d, J ) 10.1 Hz), 1.48 (9H, s), 1.13 (9H, s); 13C NMR
(CDCl3) δ 163.9, 161.1, 154.6, 141.7, 135.0, 128.0, 126.3, 125.5,
120.2, 84.0, 78.7, 58.4, 28.3, 27.5; MS (CI+) m/z 376 (M + H+,
29.6), 263 (100). HRMS (CI+) calcd for C20H30N3O4 (M + H+)
376.2236, found 376.2244. HPLC (Chiralcel AD-H, hexane/2-
propanol ) 90/10, 0.5 mL/min, 254 nm) tr(S) ) 8.8 min, tr(R) )
analysis gave [R]20 -50.0 (c 0.16, CHCl3).
D
7.2 min. A sample of 96% ee (S) by HPLC analysis gave [R]29
-23.1 (c 1.00, CHCl3).
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (C) (H.M.) and for
Scientific Research (B) (Y.T.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
D
N1,N2-Bis(tert-butyloxycarbonyl)-N1-(1-naphthyl-2-propenyl)guani-
dine (7Ac). Colorless crystals. Mp 98-99 °C (hexane). IR (CHCl3)
3386, 1711, 1610 cm-1. 1H NMR (CDCl3) δ 9.50 (2H, br s), 7.98
(1H, d, J ) 8.2 Hz), 7.83 (1H, d, J ) 7.9 Hz), 7.76 (1H, d, J ) 7.9
Hz), 7.59 (1H, d, J ) 6.1 Hz), 7.52-7.38 (4H, m), 6.46 (1H, m),
5.43 (1H, d, J ) 11.9 Hz), 5.42 (1H, d, J ) 15.9 Hz), 1.51 (9H, s),
1.07 (9H, s); 13C NMR (CDCl3) δ 164.0, 160.6, 154.9, 136.1, 135.4,
133.9, 131.3, 128.7, 128.1, 127.3, 126.4, 125.5, 124.5, 124.2, 117.8,
84.1, 78.8, 57.5, 28.3, 27.5; MS (FAB+) m/z 426 (M + H+, 12),
Supporting Information Available: Experimental procedure
1
and characterization data for all obtained compounds, and H
and 13C NMR spectra of all obtained compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO802271D
J. Org. Chem. Vol. 74, No. 1, 2009 311