Pd(0)-catalyzed sequential C-N bond formation via allylic and aromatic C-H amination of α-methylstyrenes with diaziridinone

Article abstract of DOI:10.1021/ol401935c

A novel Pd(0)-catalyzed sequential C-N bond formation process via allylic and aromatic C-H amination of α-methylstyrenes with di-tert- butyldiaziridinone, giving spirocyclic indolines in good yields, is described. Four C-N bonds and one spiro quaternary carbon are generated in a single operation.

Full text of DOI:10.1021/ol401935c

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd(0)-Catalyzed Sequential CꢀN Bond
Formation via Allylic and Aromatic CꢀH
Amination of r‑Methylstyrenes with
Diaziridinone
Thomas A. Ramirez, Qian Wang, Yingguang Zhu, Huaiji Zheng, Xingao Peng,
Richard G. Cornwall, and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
United States
yian@lamar.colostate.edu
Received July 10, 2013
ABSTRACT
A novel Pd(0)-catalyzed sequential CꢀN bond formation process via allylic and aromatic CꢀH amination of R-methylstyrenes with di-tert-butyldiaziridinone,
giving spirocyclic indolines in good yields, is described. Four CꢀN bonds and one spiro quaternary carbon are generated in a single operation.
CꢀN bond formation is very important in organic syn-
Direct CꢀH amination presents an attractive approach to
construct CꢀN bonds and remains an active area.2 In our
previous studies on the Pd(0)-catalyzed diamination3,4 of
olefins with di-tert-butyldiaziridinone (1),5,6 we have found
that terminal olefins 2 (R = CH2CH2R2) can be aminated
at allylic and homoallylic carbons to give diamination
products 3 (Scheme 1).4 This diamination process likely
proceeds via a diene intermediate, generated from the
terminal olefin via allylic CꢀH activation to form a π-allyl
Pd complex and subsequent β-hydride elimination.4 In our
efforts to further explore the reactivity of diaziridinone, we
have investigated terminal olefins which lack homoallylic
thesis, and various effective methods have been developed.1
(1) For leading reviews, see: (a) Osborn, H. M. I.; Sweeney, J. Tetra-
hedron: Asymmetry 1997, 8, 1693. (b) Lucet, D.; Le Gall, T.; Mioskowski,
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dienes using 1, see: (a) Du, H.; Zhao, B.; Shi, Y. J. Am. Chem. Soc.
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B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 7496. (b) Du, H.; Zhao, B.; Shi,
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(5) For a leading review on diaziridinones, see: Heine, H. W. In The
Chemistry of Heterocyclic Compounds; Hassner, A., Ed.; John Wiley &
Sons, Inc: New York, 1983; p 547.
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r
10.1021/ol401935c
XXXX American Chemical Society

Table 2. Substrate Scopea
Scheme 1
Table 1. Studies on Reaction Conditionsa
entry
catalyst
ligand (x mol %)
yieldb (%)
1
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
ꢀ
18
51
58
75
62
0
2
3
PPh3 (10 mol %)
4
PPh3 (20 mol %)
PPh3 (30 mol %)
PPh3 (60 mol %)
5
6
7
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
0
8
PPh3 (60 mol %)
65
36
51
0
9
P(p-MeO-Ph)3 (60 mol %)
P(p-tolyl)3 (60 mol %)
P(o-tolyl)3 (60 mol %)
P(p-F3C-Ph)3 (60 mol %)
dppp (30 mol %)
10
11
12
13
14
35
0
BINAP (30 mol %)
0
a All reactions were carried out with olefin 2a (0.40 mmol), di-tert-
butyldiaziridinone (1) (1.60 mmol), Pd(PPh3)4 (0.040 mmol) or Pd2(dba)3
(0.020 mmol), and appropriate phosphine ligand at 85 °C under Ar for 24 h
unless otherwise stated. For entry 1, di-tert-butyldiaziridinone (1) was
added in one portion. For entries 2ꢀ14, di-tert-butyldiaziridinone (1) was
slowly added over 10 h via syringe pump. b Isolated yield based on olefin 2a.
hydrogens and thus cannot form dienes under the reaction
conditions. During such studies, it has been found that
spirocyclic indolines 4can be obtained when R-methylstyrenes
were treated with di-tert-butyldiaziridinone (1) and a Pd(0)
catalyst (Scheme 1).7 The reaction likely proceeds via
a All reactions were carried out with olefin 2 (0.40 mmol), di-tert-
butyldiaziridinone (1) (1.60 mmol) (added over 10 h via syringe pump),
Pd(PPh3)4 (0.040 mmol), and PPh3 (0.080 mmol) at 85 °C under Ar for
24 h (total). b Isolated yield. The ratio of the regioisomers was deter-
mined to be >20:1 (for entries 10, 11, 13, and 15), 8:1 (for entry 12), and
10:1 (for entry 14) by 1H NMR analysis of the crude reaction mixture.
(7) For leading references on indolines derived from Pd-catalyzed
CꢀH activation: (a) Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. Org.
Lett. 2008, 10, 1759. (b) Houlden, C. E.; Bailey, C. D.; Ford, J. G.;
ꢀ
Gagne, M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem.
Soc. 2008, 130, 10066. (c) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 10806. (d) Neumann, J. J.; Rakshit, S.; Droge, T.;
a novel CꢀH activation and CꢀN bond formation process.
Herein, we report our preliminary studies on this subject.
Our initial studies were carried out with R-methylstyrene
(2a) as the test substrate. Treating 2a with di-tert-butyldi-
aziridinone (1) and 10 mol % of Pd(PPh3)4 under neat
conditions at 85 °C for 24 h gave spirocyclic indoline 4a in
€
Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 6892. (e) Nakanishi, M.;
€
Katayev, D.; Besnard, C.; Kundig, E. P. Angew. Chem., Int. Ed. 2011, 50,
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2012, 134, 3. (g) He, G.; Lu, C.; Zhao, Y.; Nack, W. A.; Chen, G. Org.
Lett. 2012, 14, 2944. (h) Saget, T.; Lemouzy, S. J.; Cramer, N. Angew.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Proposed Catalytic Cycle
18% yield (Table 1, entry 1). The yield was increased to
51% when di-tert-butyldiaziridinone (1) was added slowly
over 10h via syringe pump (Table 1, entry 2). The yield was
further improved with addition of PPh3 ligand to the
reaction system, with 20 mol % of PPh3 being optimal
(Table1, entries 3ꢀ5). No reaction was observed with PPh3
alone (Table 1, entry 6). The reaction was also investigated
with Pd2(dba)3 as catalyst (Table 1, entries 7ꢀ14). No
product was formed without additional ligand (Table 1,
entry 7). The nature of the ligand has a dramatic effect
on the product yield. Among the ligands examined, PPh3
gave the highest yield (Table 1, entry 8), and essentially no
product was obtained with P(o-tolyl)3, dppp, or BINAP
(Table 1, entries 11, 13, and 14).
As shown in Table 2, the reaction process can be
extended to various para-, meta-, di-, and trisubstituted
R-methylstyrenes 2bꢀp, giving the corresponding spiro-
cyclic indoline products 4bꢀp in 56ꢀ83% yield (Table 2,
entries 2ꢀ16). For entries 10ꢀ15, the reaction generally
occurred at the less sterically hindered position (for the
X-ray data of 4j and 4n, see the Supporting Information).
In the cases of entries 10, 11, 13, and 15, the reactions
proceeded with high regioselectivity (>20:1).
NꢀN bond of di-tert-butyldiaziridinone (1) to give four-
membered Pd(II) species 5, which then forms complex 6
with R-methylstyrene (2a). Abstraction of an allylic hydro-
gen from 6 leads to π-allyl Pd complex 7,8,9 which affords
allyl urea-ligated Pd(0) intermediate 8 via reductive
elimination.10 Reaction of intermediate 8 with another
equivalent of 1 provides 9, which undergoes a Pd(II)-
catalyzed cyclization to give 10.11,12 Subsequently, 10
undergoes an intramolecular aromatic CꢀH activation
to form urea 11 and pallada(II)cycle 12,13 which inserts
into the NꢀN bond of 1 to give pallada(IV)cycle 13.
Reductive elimination of pallada(IV)cycle 13 leads to
eight-membered pallada(II)cycle 14a and/or 14b (path-
waya), which istransformedto 16a and/or 16bbyreleasing
tert-butyl isocyanate (15).14 Upon reductive elimination,
16a and/or 16b is converted to spirocyclic indoline 4a
with the regeneration of the Pd(0) catalyst. Alternatively,
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with N and O nucleophiles, see: (a) Hegedus, L. S. Tetrahedron 1984, 40,
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While a precise understanding of the reaction mecha-
nism awaits further study, a plausible catalytic pathway
is proposed in Scheme 2. The Pd(0) first inserts into the
Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46, 1910.
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C

pallada(IV)cycle 13 releases a molecule of tert-butyl iso-
cyanate (15) to form Pd(IV)-nitrene 1715 (pathway b),
which undergoes two consecutive reductive eliminations
to give product 4a via 16a and/or 16b and to regenerate the
Pd(0) catalyst.
complex 7 is very likely to be involved in this process.
Attempts to isolate any reaction intermediates were un-
successful. Allyl urea 18 was subsequently prepared and
subjected to the reaction conditions. It was found that 18
did cyclize to provide indoline 4a (eq 2), which is also
in agreement with the reaction mechanism described in
Scheme 2. A known palladacycle 1916 was also prepared
and was found to be catalytically active. Treating R-
methylstyrene (2a) with di-tert-butyldiaziridinone (1) in
the presence of 10 mol % of 19 and 60 mol % of PPh3 at
85 °C for 24 h gave indoline 4a in 77% yield along with
small amounts of indoline 20 (eq 3). When stoichiometric
amounts of 19 were used, indolines 4a and 20 were ob-
tained in 72% and 76% yield, respectively. These results
suggest that palladacycle 12 is a likely intermediate in the
catalytic cycle and can be converted into the indoline 4a.
Insummary, we have discovered a novel Pd(0)-catalyzed
CꢀN bond formation process of R-methylstyrenes with di-
tert-butyldiaziridinone (1) via sequential allylic and aro-
matic CꢀH amination. Various R-methylstyrenes can be
converted to spirocyclic indolines in good yields with the
generation of four CꢀN bonds and one spiro quaternary
carbon in a single operation. The ability of di-tert-butyl-
diaziridinone to be oxidatively inserted into a R2Pd(II)
species further illustrates its versatile reactivity and opens
up more opportunities for new reaction development
with this class of compounds. Such studies are currently
underway.
To gain some insight into the reaction mechanism,
additional experiments were performed (Schemes 3).
Scheme 3
Acknowledgment. We are grateful for the generous
financial support from the General Medical Sciences of
the National Institutes of Health (GM083944-06).
When deuterium-labeled R-methylstyrene 2a-d was sub-
jected to the standard reaction conditions, equal amounts
of indoline products 4a-d and 4a-d0 were obtained in 50%
yield (Scheme 3, eq 1). This result suggests that π-allyl Pd
Supporting Information Available. Experimental pro-
cedure, characterization of all compounds, and crystal-
lographic information file for compounds 4a,j,n, and 19.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX