Pd-Catalyzed Alkene Diamination Reactions of Nitrogen Electrophiles: Synthesis of Cyclic Guanidines and Ureas Bearing Dialkylaminomethyl Groups

Article abstract of DOI:10.1021/acs.orglett.8b01289

The Pd-catalyzed coupling of N-allylguanidines or N-allylureas with O-benzoylhydroxylamine derivatives affords cyclic guanidines or cyclic ureas bearing dialkylaminomethyl groups. The desired products are obtained in good yield, and substrates bearing substituents at the allylic position are transformed with moderate diastereoselectivity. The mechanism of these reactions appears to involve anti-aminopalladation of the alkene, followed by a rare sp³C-sp³N bond-forming reductive elimination from an alkylpalladium complex that contains β-hydrogen atoms.

Full text of DOI:10.1021/acs.orglett.8b01289

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Pd-Catalyzed Alkene Diamination Reactions of Nitrogen
Electrophiles: Synthesis of Cyclic Guanidines and Ureas Bearing
Dialkylaminomethyl Groups
Luke J. Peterson, Janelle K. Kirsch, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
*
S Supporting Information
ABSTRACT: The Pd-catalyzed coupling of N-allylguanidines
or N-allylureas with O-benzoylhydroxylamine derivatives
affords cyclic guanidines or cyclic ureas bearing dialkylamino-
methyl groups. The desired products are obtained in good
yield, and substrates bearing substituents at the allylic position are transformed with moderate diastereoselectivity. The
3
3
mechanism of these reactions appears to involve anti-aminopalladation of the alkene, followed by a rare sp C−sp N bond-
forming reductive elimination from an alkylpalladium complex that contains β-hydrogen atoms.
ver the past 14 years, our group has reported a series of
Pd-catalyzed alkene difunctionalization reactions be-
an appended dialkylaminomethyl group (4), which are7
subunits displayed in some biologically active compounds.
The final step in the alkene diamination catalytic cycle would
O
tween aryl or alkenyl halides or triflates and alkenes bearing
1
3
3
pendant nucleophiles. For example, treatment of an N-allyl
be an sp C−sp N bond-forming reductive elimination from an
urea or guanidine derivative (1) with an aryl halide or triflate
alkylpalladium complex, which is a very rare organometallic
2
8
affords heterocyclic product 2 in good yield (eq 1). These
transformation, and was expected to be challenging to
transformations are effective with a broad range of
nucleophiles, the reactions are stereospecific with respect to
alkene geometry, and substrates bearing substituents on the
alkene or the alkyl tether are generally transformed with good
to excellent levels of diastereoselectivity. Despite the utility of
these transformations, to date, all reactions have involved the
use of carbon-centered electrophiles, which leads to the
formation of one C−C bond and one carbon−heteroatom
bond during the alkene addition.
achieve. However, recent studies on alkane C−H functional-
ization with these electrophiles suggested that this reductive
8a,9
elimination step may be possible.
In addition, although
Wang has reported an analogous, Cu-catalyzed alkene
1
diamination reaction involving N-alkoxypentamides or N -
2
10−12
allyl-N -methoxyureas as substrates,
the Cu-catalyzed
reactions reported thus far are not stereospecific, with respect
to alkene geometry, because of the radical character of an
10
intermediate alkylcopper complex (eq 3):
Thus, it appeared that the Pd-catalyzed process could have
advantages over the Cu-catalyzed reactions, since our Pd-
catalyzed alkene carboamination reactions are stereospecific,
and we anticipated that the new diamination reactions would
also be stereospecific.
In order to explore the feasibility of Pd-catalyzed alkene
diamination reactions involving nitrogen electrophiles, we first
examined the coupling of 7a with morpholino benzoate (3a)
to afford cyclic guanidine product 8a (see Table 1). Initially,
In recent years, the use of O-acylated hydroxylamine
derivatives as nitrogen-centered electrophiles 3 in metal-
3
we employed catalysts derived from Pd(OAc) and the ligands
2
catalyzed reactions has attracted considerable attention. We
DPE-Phos, CPhos, and XantPhos, because these ligands
provided good to excellent results in alkene carboamination
were interested in investigating the utility of these electro-
4
−6
philes in heterocycle-forming alkene diamination reactions
of substrates such as 1 that are mechanistically related to our
Pd-catalyzed alkene carboamination reactions (eq 2). These
transformations would provide heterocyclic products bearing
Received: April 23, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01289
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization Studies
the formation of the desired product in a measurable, but low
13
yield. Subsequently, we turned our attention to electron-
poor monodentate phosphines, because ligands such as
P(C F ) have provided good results in other Pd-catalyzed
6
5 3
9
a,14
transformations of nitrogen electrophiles,
and it seemed
3
3
that the electron-poor ligand may accelerate the sp C−sp N
1
5
bond-forming reductive elimination step. The use of
P(C F ) as the ligand resulted in an improved 30% yield
b
yield
entry
1
[Pd]
ligand (L)
DPE-Phos
catalyst loading
2 mol % [Pd]
(%)
6 5 3
of 8a, and after surveying several palladium sources, we found
Pd(OAc)2
13
that the use of Pd(acac) led to a further increase to 60%
2
4
mol % L
yield. The combination of P[3,5-(CF ) C H ] as the ligand
3
2
6
3 3
and Pd(acac) as the precatalyst was even better, with 8a
generated in 80% yield. Finally, we examined the
biarylphosphine JackiePhos, which contains two 3,5-
2
2
3
4
5
6
7
8
9
Pd(OAc)2
CPhos
2 mol % [Pd]
mol % L
0
0
8
(
CF ) C H groups on the phosphorus atom and has
3 2 6 3
Pd(OAc)2
XantPhos
P(C F )
2 mol % [Pd]
mol % L
2
previously been shown to promote challenging sp C−N
8
16
bond-forming reductive elimination; we were delighted to
obtain a 95% NMR yield of 8a. With this catalyst system, we
were able to decrease the amount of electrophile used from 4
equiv to 3 equiv, but the use of 2 equiv or less of the
electrophile resulted in diminished yields.
Pd(OAc)2
2 mol % [Pd]
mol % L
30
0
6
5
3
3
3
3
8
Pd (dba)3
2
P(C F )
4 mol % [Pd]
6 mol % L
6 5
Once the satisfactory conditions were in hand, we
conducted a few additional experiments to further examine
the influence of precatalyst structure on yield. Although the
1
Pd(TFA)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
P(C F )
4 mol % [Pd]
6 mol % L
40
60
80
95
6
5
Pd(acac) /JackiePhos catalyst system provided excellent
2
1
results (entry 10 in Table 1), the use of Pd (dba) as a
2
3
precatalyst for this reaction completely inhibited product
formation (entry 11 in Table 1). The addition of 6 mol % dba
to the otherwise optimal conditions (entry 12 in Table 1)
resulted in the formation of 8a in only 25% yield. Use of the
Buchwald G3-JackiePhos catalyst precursor in place of
P(C F )
4 mol % [Pd]
6 mol % L
6
5
1
P[C H -3,5-(CF ) ]
3 2 3
4 mol % [Pd]
6 mol % L
6
3
1
Pd(acac) failed to produce significant amounts of the desired
2
product (≤5%; see entries 13 and 14 in Table 1). However,
when 8 mol % acac (2,4-pentanedione) was added to a
reaction in which the G3-JackiePhos complex was used as
precatalyst, 8a was generated in 35% yield. These results
JackiePhos
JackiePhos
JackiePhos
4 mol % [Pd]
6 mol % L
1
c
10
11
12
4 mol % [Pd]
6 mol % L
95
indicate that (a) the failure of Pd (dba) to serve as a viable
1
2
3
precatalyst is probably due to inhibition by the dba ligand
rather than the zerovalent oxidation state of that complex; and
c
Pd (dba)3
2
4 mol % [Pd]
6 mol % L
0
(
b) acac plays a key role in these reactions, either by
1
facilitating reactivity of an intermediate along the catalytic
cycle or, more likely, by inhibiting catalyst deactivation.
Then, we explored the scope of the Pd-catalyzed coupling
reactions of N-cyano and N-tosylguanidine substrates 7a−7d
with several different electrophiles. As shown in Table 2, these
transformations are effective with O-benzoylhydroxylamine
electrophiles derived from morpholine (3a), piperidine (3b),
and N-boc piperazine (3c). However, efforts to employ an
acyclic electrophile derived from N-methyl benzylamine led to
the formation of a complex mixture of products. Reactions of
substrates 7c−7d bearing an allylic methyl group proceeded
to afford 8f−8h in good yield and moderate diastereose-
lectivity (3:1 diastereomeric ratio (dr)). These diastereose-
lectivities are comparable to those obtained in analogous Pd-
catalyzed carboamination reactions of 7c and 7d with aryl
c
Pd(acac)2
JackiePhos + dba
4 mol % [Pd]
25
1
6
6 mol % L
mol % dba
c
1
3
G3-JackiePhos JackiePhos
4 mol % [Pd]
<5
d
1
6 mol % L
c
1
1
4
5
G3-JackiePhos no added ligand
4 mol % [Pd]
5
c
G3-JackiePhos JackiePhos + acac
4 mol % [Pd]
35
d
1
8
6 mol % L
mol % acac
a
Conditions: 1.0 equiv 7a, 4.0 equiv 3a, 2 equiv Cs CO , [Pd], ligand
L), dioxane (0.1 M), 100 °C, 16 h. Yields were determined by H
NMR using 1,10-phenanthroline as an internal standard. The reaction
was conducted using 3 equiv 3a instead of 4 equiv. The reaction was
conducted with 12 mol % added JackiePhos (plus the 4 mol % of
JackiePhos bound to the G3 complex).
2
3
b
1
(
c
2a
bromides. Attempts to employ substrates bearing either 1,1-
d
or 1,2-disubstituted alkenes, thus far, have been unsuccessful.
We also briefly explored the coupling of urea substrates
9a−9c to afford 10a−10f. As shown in Table 3, the reactions
of 9a proceeded smoothly with electrophiles derived from
morpholine (90% yield on a 0.1 mmol scale and 76% yield on
a 1.0 mmol scale) and piperidine (83% yield). However, use
of electrophile 3c derived from N-boc piperazine led to a
1
,2
reactions of 7a and related nucleophiles.
No desired
product was obtained with the CPhos or XantPhos ligands,
but we were gratified to find that the use of DPE-Phos led to
B
DOI: 10.1021/acs.orglett.8b01289
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Diamination of N-Allylguanidines
addition product d-8a in 67% yield and 3:1 dr. The reactions
of urea substrate d-9a and N-tosylguanidine d-7b with
morpholino benzoate also proceeded via anti-addition to the
alkene, but with higher diastereoselectivity (6:1 dr in both
cases). The coupling of piperidin-1-yl benzoate 3b with d-7b
gave slightly higher diastereoselectivity (7:1 dr) than was
obtained with morpholino benzoate. Thus, in contrast to the
related copper-catalyzed diamination reactions, the Pd-
catalyzed alkene diamination reactions are stereospecific,
although the transfer of stereochemical information from
substrate to product is thus far imperfect (but arguably
synthetically useful).
10
b
c
entry
P
X
R
diastereomeric ratio, dr
yield (%)
Based on the alkene addition stereochemistry, we propose
that these new Pd-catalyzed alkene diamination reactions
proceed via the catalytic cycle shown in Scheme 1. Initial
1
2
3
4
5
6
7
8
CN
CN
CN
Ts
O
H
91 (8a)
92 (8b)
61 (8c)
86 (8d)
77 (8e)
75 (8f)
81 (8g)
88 (8h)
CH2
NBoc
O
H
H
ligation and reduction of the Pd(acac) precatalyst leads to
H
2
the formation of a Pd(0) complex, which then undergoes
Ts
CH2
O
H
oxidative addition to the O-benzoyl hydroxylamine 3a to
CN
CN
Ts
Me
Me
Me
3:1 (4:1)
3:1
17
afford intermediate 11. Coordination of the alkene to the
Pd-complex followed by deprotonation and anti-amino-
CH2
O
3:1
18
a
palladation of 12 then affords 13, which undergoes C−N
bond-forming reductive elimination to yield d-10a with
concomitant regeneration of the Pd(0) catalyst. Although
we currently favor this proposed mechanism, at this point, we
cannot rule out an alternative pathway involving the oxidation
of 13 to Pd(IV) complex 14, followed by reductive
elimination to afford the product with the formation of 11
to close the catalytic cycle.
The minor stereoisomer observed in these reactions most
likely originates via one of two pathways: (a) competing syn-
aminopalladation via a palladium bis(amido) complex; or (b)
erosion of the stereochemistry of intermediate 13 (or 14, as
the case may be) via β-hydride elimination/reinsertion to
generate a tertiary α-amino palladium complex, which can
Conditions: 1.0 equiv 7, 3.0 equiv 3, 2 equiv Cs CO , 4 mol %
2
3
Pd(acac) , 16 mol % JackiePhos, dioxane (0.1 M), 100 °C, 16 h.
Reactions were conducted on a 0.1 mmol scale. Diastereomeric ratios
were determined by H NMR analysis. Numbers shown in parentheses
are dr values for the crude reaction mixture in cases where the crude
and isolated dr differed. Isolated yield (average of two or more
experiments).
2
b
1
c
a
Table 3. Diamination of N-Allylureas
undergo rotation around the C−CH D bond followed by a
2
second β-hydride elimination/reinsertion to invert the stereo-
19
b
c
genic center. In order to probe this question, we sought to
slow the rate of potential β-hydride elimination from 13 by
replacing the H atom on the internal alkene carbon with a
deuterium atom (R = D). We hoped that this substitution
would either lead to higher stereocontrol, therefore suggesting
that the minor stereoisomer originates from β-hydride
entry
Y
X
R
diastereomeric ratio, dr
yield (%)
1
2
3
4
NO2
NO2
NO2
NO2
Cl
O
H
90 (10a)
83 (10b)
46 (10c)
32 (10d)
45 (10e)
14 (10f)
CH2
NBoc
O
H
H
Me
H
2:1
d
5
d
O
20
elimination, or would lead to no change in stereoselectivity,
6
Cl
CH2
H
which would imply that the modest stereocontrol is due to
a
Conditions: 1.0 equiv 9, 3.0 equiv 3, 2 equiv Cs CO , 4 mol %
21
2
3
competing syn- vs anti-aminopalladation. As such, doubly
Pd(acac) , 16 mol % JackiePhos, dioxane (0.1 M), 100 °C, 16 h.
Reactions were conducted on a 0.1 mmol scale. Diastereomeric ratios
were determined by H NMR analysis. Isolated yield (average of two
or more experiments). The reaction was conducted with 4 mol %
2
deuterated alkene substrate 15 was prepared and subjected to
our standard reaction conditions. As shown in eq 4, this
transformation afforded 16 in 64% yield and 6:1 dr, which is
comparable to that obtained in the reaction of d-9a. Thus, the
minor stereoisomer appears to result from competing syn-
aminopalladation.
b
1
c
d
Pd(acac) and 6 mol % JackiePhos.
2
modest yield of the desired product. Although the presence of
a methyl group at the allylic position was well-tolerated in the
reactions of guanidine nucleophiles 7c and 7d (Table 2,
entries 6−8), the coupling of analogous urea substrate 9b
proceeded in low yield (32%) to afford 10d with 2:1 dr. Use
of the substrate 9c, which contains an N-p-chlorophenyl
group, led to lower yields than were observed in reactions of
9
a, because of competing decomposition of the urea substrate
to give N-allylbenzylamine.
In conclusion, we have developed a new class of Pd-
catalyzed alkene diamination reactions that involve the
coupling of O-benzoyl hydroxylamine-derived electrophiles
with N-allylguanidine or urea derivatives. The transformations
proceed via stereospecific anti-addition of the two N atoms to
In order to gain insight into the mechanism and
stereospecificity of these new transformations, we examined
the reactivity of deuterated substrates d-7a, d-7b, and d-9a. As
shown in Table 4, the coupling of d-7a with 3a afforded anti-
C
DOI: 10.1021/acs.orglett.8b01289
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 4. Alkene Addition Stereochemistry
b
entry
Y
R
X
diastereomeric ratio, dr
yield (%)
1
2
3
4
N−CN
O
Bn
O
3:1
6:1
6:1
7:1
67 (d-8a)
75 (d-10a)
75 (d-8d)
77 (d-8e)
C H -p-NO
6
O
4
2
N−Ts
N−Ts
Bn
O
Bn
CH2
a
Conditions: 1.0 equiv 7a and 7b or 9a, 3.0 equiv 3a or 3b, 2 equiv Cs CO , 4 mol % Pd(acac) , 16 mol % JackiePhos, dioxane (0.1 M), 100 °C, 16
2
3
2
b
h. Reactions were conducted on a 0.1 mmol scale. Isolated yield (average of two or more experiments).
Scheme 1. Catalytic Cycle: Working Hypothesis
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the University of Michigan for financial
support of this work. We also thank Elsa M. Hinds
(
University of Michigan) for preparation and characterization
of substrate 9c.
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Supporting Information
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■
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DOI: 10.1021/acs.orglett.8b01289
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(
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2
3
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(
(
19) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468.
20) β-hydride elimination reactions from Pd typically exhibit large
primary kinetic isotope effects (over 5), so substitution of D for H in
intermediate 13 should decrease the rate of β-hydride elimination
without having much impact on the rate of reductive elimination.
Therefore, if formation of the minor stereoisomer derives from β-
hydride elimination from 13, substitution of D for H should improve
stereocontrol by slowing that process. See: Mueller, J. A.; Goller, C.
P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724.
(
21) For a related experiment in the context of guanidine
carboamination, see ref 2a. In the present work, a deuterium atom
was used instead of a methyl group at the internal alkene carbon,
because, thus far, substrates bearing substitution at this position have
been unreactive in this system.
E
DOI: 10.1021/acs.orglett.8b01289
Org. Lett. XXXX, XXX, XXX−XXX