Pd(II)-catalyzed allylic C-H amination for the preparation of 1,2- and 1,3-cyclic ureas

Article abstract of DOI:10.1021/ol5037453

A general synthesis of 1,2- and 1,3-cyclic ureas is accomplished by intramolecular allylic C-H amination employing Pd(TFA)₂/bis-sulfoxide as a catalyst. By careful modification of substrates and catalyst, a variety of 1,2-cyclic ureas are accessible from not previously employed terminal olefins substituted in allylic or vinylic positions. Furthermore, MS4A is found to be an effective additive for the synthesis of 1,3-cyclic ureas in good yields and excellent diastereoselectivities.

Full text of DOI:10.1021/ol5037453

Letter
pubs.acs.org/OrgLett
Pd(II)-Catalyzed Allylic C−H Amination for the Preparation of 1,2-
and 1,3-Cyclic Ureas
Yasuhiro Nishikawa,* Seikou Kimura, Yuri Kato, Natsuka Yamazaki, and Osamu Hara*
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
S
* Supporting Information
ABSTRACT: A general synthesis of 1,2- and 1,3-cyclic ureas
is accomplished by intramolecular allylic C−H amination
employing Pd(TFA)2/bis-sulfoxide as a catalyst. By careful
modification of substrates and catalyst, a variety of 1,2-cyclic
ureas are accessible from not previously employed terminal
olefins substituted in allylic or vinylic positions. Furthermore,
MS4A is found to be an effective additive for the synthesis of
1,3-cyclic ureas in good yields and excellent diastereoselectivities.
1,2- and 1,3-cyclic ureas and their derivatives such as guanidines
are important motifs in natural products and pharmaceuticals.1
In addition, these motifs can be lead compounds to structurally
and biologically diverse 1,2- and 1,3-diamines.2 Among the
various useful approaches to cyclic ureas, C−H amination of the
corresponding acyclic ureas seems to be attractive since the
preparation of substrates and their C−N functionalization can be
performed with minimal functional group manipulations.3−6
One of the most powerful methods is Rh-catalyzed C−H
amination to afford 1,2- and 1,3-diamines through the
corresponding ureas, guanidines, sulfamates, and sulfamides.7
While a variety of C−H bonds can be functionalized via Rh-
nitrenoids, one drawback is that olefin aziridination outcompetes
the desired allylic C−H insertion in cases where homoallyl and
bis-homoallyl derivatives are used.7b−d On the other hand, Pd-
catalyzed amination favors allylic C−H bond functionalization
and further functionalization of the resulting olefin moiety.
Pioneering work in this field is the Pd(II)/bis-sulfoxide catalyzed
C−H amination first reported by White et al. to produce 1,2- and
1,3-cyclic carbamates leading to 1,2-anti and 1,3-syn amino
alcohols (eq 1).8,9 Very recently, the same group reported a new
synthetic method for 1,2-cyclic ureas by an olefin isomerization/
amination protocol employing a Pd(II) catalyst with a Lewis acid
cocatalyst (eq 2).10
Inspired by these results, we started to investigate the synthesis
of a variety of cyclic ureas, because of not only their inaccessibility
by Pd(II) catalyzed C−H oxidation but also the limited
reaction in terms of yield as well as reaction time (entries 2−4).
availability of suitable substrates for olefin isomerization/
This is in contrast with the synthesis of cyclic carbamates in
amination, yielding 1,2-cyclic ureas only. In particular, substrates
that are branched at the allylic (R2) or vinylic (R3) positions have
which the use of Pd(TFA)2 led to insignificant amounts of
yet to be employed in Pd(II) catalyzed C−H oxidation (eq 3).8a
cyclized product unless an external acetate source was added
(Scheme 2, vide infra).8a Next, we turned our attention to the
Furthermore, it has yet to be applied to the preparation of 1,3-
cyclic ureas (eq 4).
effect of the protecting group on the cyclization reaction. Boc
protected acyclic urea 1b gave a better yield than that of 1a (entry
5). On the other hand, unprotected (1c) and Bn protected
An initial attempt at the cyclization of 1a under the same
conditions as used in the synthesis of cyclic carbamates8
furnished cyclic urea 2a in an unsatisfactory yield (Table 1,
entry 1). While replacing Pd(OAc)2 with PdCl2 further reduced
the yield, the use of Pd(TFA)2 dramatically improved this
Received: December 29, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol5037453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
5). Interestingly, opposite diastereoselectivities were observed
between entry 3 and entries 4−5.13 This might be explained by
the coordination of the phenyl group to the π-allyl Pd complex
during cyclization, which preferentially leads to syn-2e over
sterically favored anti-2e (Figure 1). Similarly, bulky substituents
on the homoallylic position influence the diastereoselectivities to
afford only anti products in high yield (entries 6 and 7).
Table 1. C−H Oxidation for 1,2-Cyclic Ureas by C−H
Oxidation
a
b
entry
PdX2
protecting group
time
% yield
1
2
3
4
5
6
7
OAc
Cl
Cbz
Cbz
Cbz
Cbz
Boc
H
(1a)
(1a)
(1a)
(1a)
(1b)
(1c)
(1d)
48
48
48
24
24
48
48
2a (38)
2a (13)
2a (90)
2a (85)
TFA
TFA
TFA
TFA
TFA
2b (93)
Figure 1. Plausible transition models in cyclization.
2c (ND)
2d (ND)
Bn
In the previous studies of Pd-catalyzed C−H amination, high
yielding reactions have been limited to substrates bearing an allyl
group.8 To test the versatility of the protocol in our study, we
demonstrated C−H amination of challenging substrates such as
homoallylureas substituted in allylic and vinylic positions
(Scheme 1). Gratifyingly, the methyl group and an even more
a
Reactions were performed with 0.2 mmol of acyclic urea (1a−d), 10
mol % of Pd(II)/bissulfoxide complexes, and 1.0 equiv of phenyl-1-
b
benzoquinone (PhBQ) in THF (0.3 mL) at 45 °C. Determined by
1H NMR analysis.
acyclic urea 1d formed no cyclized product (entries 6 and 7).
These results implied that the acidity of the urea is an important
factor in this reaction as an electron-withdrawing group on the
urea enhances the acidity of the N−H on the urea.8b
Next, we examined the range of substrates for the synthesis of
1,2-cyclic ureas (Table 2). The acyclic urea bearing a phenyl
Scheme 1. C−H Oxidation of Substrates Branched at the
Allylic or Vinylic Positions
Table 2. Substrate Range for the Synthesis of 1,2-Cyclic Ureas
c
d
entry
R1
H (1b)
% yield
dr (anti:syn)
a
1
2b (87)
2e (75)
2e (65)
2f (53)
2g (99)
2h (79)
2i (69)
−
a
2
Ph (1e)
38:62
33:67
65:35
65:35
>95:5
>95:5
b
bulky n-propyl group on the allylic position had no deleterious
effect on C−H amination to give the corresponding cyclic ureas
2j and 2k having quaternary carbon centers. In addition, a cyclic
urea 2l bearing a 2-styryl group could be synthesized using the
same protocol.
3
Ph (1e)
b
4
CH2CH2Ph (1f)
nPr (1g)
iPr (1h)
b
5
b
6
b
7
tBu (1i)
With the successful synthesis of a variety of 1,2-cyclic ureas in
hand, we anticipated that 1,3-cyclic ureas might be obtained in an
analogous fashion (Table 3). However, the application of the
same conditions as those used for 1,2-cyclic ureas to acyclic bis-
homoallylurea 3a gave 1,3-cyclic urea 4a in poor yield (entry 1).
Increasing the reaction time, reaction temperature, or oxidant
equivalents did not improve the reaction (entries 2−4).
Fortunately, we found that addition of MS4A accelerated the
reaction dramatically to afford the desired product in high yield
(entries 5 and 6). As MS4A was usually employed as a
dehydrating agent, an experiment to check the influence of
water on the reaction was done (entry 7). Almost the same
product yields were observed for entries 4 and 7 implying that
water does not impair this C−H amination. Thus, the effect of
MS4A on the reaction could not be simply explained as drying
a
Method A: Isolated Pd(TFA)2/bis-sulfoxide complex was used.
Method B: Pd(TFA)2/bis-sulfoxide complex was prepared in the
b
reaction vessel before use. See Supporting Information for more
c
d
details. Isolated yields. Determined by 1H NMR of the crude
products.
group on the homoallylic position was cyclized in good yield and
moderate diastereoselectivity (entry 2).11 At this stage, another
method in which the Pd(TFA)2/bis-sulfoxide complex is
prepared in situ and used without isolation (Method B) was
compared with the previous method using the isolated complex
(Method A).12a We subsequently adopted the simpler method B
because both methods resulted in similar yields and selectivities
(entries 2 and 3). Further investigation revealed that alkyl-
substituted substrates reacted in a similar fashion (entries 4 and
B
DOI: 10.1021/ol5037453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Finally, the plausible catalytic cycle was speculated on the basis
of our experimental results and mechanistic investigations of
Pd(II)/bis-sulfoxide catalysis reported previously (Scheme
2).8,10,12 The catalytic cylcle starts with alkene coordination to
Table 3. C−H Oxidation for 1,3-Cyclic Urea 4a
Scheme 2. Plausible Catalytic Cycle
b
entry PhBQ (equiv) temp (°C) time (h)
additive
yield (%)
1
2
3
4
5
6
7
1
1
1
2
2
2
2
45
45
60
45
45
45
45
24
48
48
48
48
24
48
−
−
−
−
18
24
31
31
87
97
24
c
c
c
c
c
d
d
MS4A
MS4A
e
H2O
a
b
c
1
0.2 mmol scale. Determined by H NMR analysis. Concentration
d
e
of 3a was 0.33 M. Powdered MS4A (50 mg) was used. 1 equiv.
the reaction medium, though the actual mechanism is still
unclear. To the best of our knowledge, this is the first example of
the synthesis of a 1,3-cyclic urea via allylic C−H oxidation.14
Having established the optimal conditions for the synthesis of
1,3-cyclic urea 4a, we next applied them to various acyclic bis-
homoallylureas (Table 4). Cyclization of the phenyl-substituted
Table 4. Substrate Range for the Synthesis of 1,3-Cyclic
a
Ureas
the Pd(TFA)2/bis-sulfoxide complex followed by C−H cleavage
to produce the π-allylPd species A and trifluoroacetic acid.8a,10 At
this stage, a nitrogen nucleophile is thought to be formed by
Pd(II) counterion-mediated deprotonation of a NH moiety to
achieve the desired cyclization.8 We envisioned effective
coordination of trifluoroacetic acid with the imide moiety in B,
which could enhance the acidity of the NH proton. The resulting
NH proton should be more susceptible to deprotonation even
with a weakly basic trifluoroacetate ion on the π-allylPd complex
B. The formation of the cyclized product C is accompanied by
the release of the Pd(0) complex and trifluoroacetic acid, which is
oxidized by PhBQ to regenerate a Pd(II) catalyst.16 However,
further studies must be done to prove the above considerations.
In conclusion, we have demonstrated that a Pd(TFA)2/bis-
sulfoxide system is effective for intramolecular allylic C−H
amination to yield a variety of 1,2-cyclic ureas. Acyclic
homoallylureas substituted in allylic or vinylic positions can be
employed in this reaction to give synthetically useful cyclic ureas
bearing quaternary carbon centers or styryl groups. Furthermore,
the combination of MS4A with the Pd(TFA)2/bis-sulfoxide
system enables the C−H amination via allylic C−H oxidation to
afford 1,3-cyclic ureas for the first time. Excellent 1,3-
diastereoselectivity for a broad range of substrates adds value
to this procedure, giving access to biologically active compounds
and natural products containing 1,3-cyclic ureas and 1,3-
diamines.15
b
c
entry
R1
R2
yield (%)
dr (anti:syn)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
H
H
H
4a (86)
4b (46)
4c (52)
4d (69)
4e (83)
4f (81)
4g (84)
−
Ph
Et
>95:5
>95:5
>95:5
>95:5
>95:5
−
H
CH2CH2Ph
H
iPr
tBu
H
H
H
3g
Me
a
b
0.2 mmol scale with powdered MS4A (50 mg). Isolated yields.
Determined by H NMR of the crude products.
c
1
acyclic urea took place in modest yield (entry 2), in contrast to
the formation of the analogous 1,2-cyclic urea. It is thought that
the coordination of the phenyl group to the π-allyl Pd complex
discussed above led to a conformation unfavorable for its
cyclization. A variety of substrates having sterically different alkyl
groups were effectively oxidized and aminated in modest to good
yields (entries 3−6). It is noteworthy that in all cases these
cyclizations proceeded with excellent diastereoselectivity to give
1,3-anti cyclic ureas.13 As 1,3-stereoinduction is generally more
difficult to achieve than 1,2-induction, this method is valuable for
the stereoselective synthesis of 1,3-cyclic urea and diamine
derivatives. Additionally, 3g, incorporating a gem-dimethyl
group at the homoallylic position that can sterically hinder C−
H activation due to its bulkiness was successfully cyclized to
include a highly congested stereocenter in good yield (entry 7).
ASSOCIATED CONTENT
■
S
* Supporting Information
All experimental procedures and spectroscopic data of substrates
and cyclized compounds in Scheme 1 and Tables 2−4. This
material is available free of charge via the Internet at http://pubs.
acs.org.
C
DOI: 10.1021/ol5037453
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) For Pd(OAc)2/bis-sulfoxide-catalyzed intramolecular C−H
amination, see: (a) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc.
2007, 129, 7274. (b) Rice, G. T.; White, M. C. J. Am. Chem. Soc. 2009,
131, 11707. (c) Qi, X. B.; Rice, G. T.; Lall, M. S.; Plummer, M. S.; White,
M. C. Tetrahedron 2010, 66, 4816. (d) Jiang, C.; Covell, D. J.; Stepan, A.
F.; Plummer, M. S.; White, M. C. Org. Lett. 2012, 14, 1386.
(9) For selected examples of Pd(OAc)2/bis-sulfoxide-catalyzed C−H
oxidation, see: (a) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004,
126, 1346. (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, M. C.
J. Am. Chem. Soc. 2005, 127, 6970. (d) Reed, S. A.; White, M. C. J. Am.
Chem. Soc. 2008, 130, 3316. (e) Covell, D. J.; White, M. C. Angew. Chem.,
Int. Ed. 2008, 47, 6448. (f) Stang, E. M.; Christina White, M. Nat. Chem.
2009, 1, 547. (g) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2011,
133, 12584. (h) Osberger, T. J.; White, M. C. J. Am. Chem. Soc. 2014,
136, 11176.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: yasuhiro@meijo-u.ac.jp.
*E-mail: oshara@meijo-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Young Scientists (B) (26810063) from the Japan Society for the
Promotion of Science (JSPS).
(10) Strambeanu, I. I.; White, M. C. J. Am. Chem. Soc. 2013, 135, 12032.
(11) The acyclic tosylcarbamate bearing phenyl group on the
homoallylic position was reported to furnish 4-phenyl-1,3-butadiene
by elimination of tosylcarbamate in Pd(OAc)2/bis-sulfoxide catalysis.
See ref 8a.
(12) (a) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.; Messaoudi, A.;
Poli, G. Chem.Eur. J. 2009, 15, 11078. (b) Rajabi, J.; Lorion, M. M.;
Ly, V. L.; Liron, F.; Oble, J.; Prestat, G.; Poli, G. Chem.Eur. J. 2014, 20,
1539.
(13) For determination of relative stereochemistry of 1,2- and 1,3-
cyclic ureas, see Supporting Information.
(14) 1,3-Cyclic sulfamides has been synthesized effectively by Rh-
catalyzed C-H insertion. See ref 7d.
(15) The synthesis of 1,3-diamine from 4b was reported following
literature procedure. See: Muorgen, M.; Bretzke, S.; Li, P.; Menche, D.
Org. Lett. 2010, 12, 4494.
(16) No dienes formed from β-hydride elimination were observed in
this study. This fact particularly in Tables 3 and 4 may imply the rate of
cyclization is sufficiently fast after the formation of π-allylPd complexes
with Pd(TFA)2; see: Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011,
133, 14892.
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