Palladium-catalyzed difunctionalization of enol ethers to amino acetals with aminals and alcohols

Article abstract of DOI:10.1021/ja410611b

A new strategy was developed for intercepting the palladium-alkyl species generated in Heck reaction via nucleophilic addition prior to the step of migratory insertion, which leads to a new palladium-catalyzed difunctionalization of enol ethers with aminals and alcohols to afford amino acetals. Mechanistic studies suggested that the cationic cyclometalated Pd(II) complex generated by the oxidative addition of aminal to a Pd(0) species was crucial for this unusual transformation.

Full text of DOI:10.1021/ja410611b

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Difunctionalization of Enol Ethers to Amino
Acetals with Aminals and Alcohols
Yinjun Xie, Jianhua Hu, Pan Xie, Bo Qian, and Hanmin Huang*
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, People’s Republic of China
S
* Supporting Information
Scheme 1. New Strategy for Difunctionalization of Alkenes
ABSTRACT: A new strategy was developed for intercept-
ing the palladium−alkyl species generated in Heck reaction
via nucleophilic addition prior to the step of migratory
insertion, which leads to a new palladium-catalyzed
difunctionalization of enol ethers with aminals and
alcohols to afford amino acetals. Mechanistic studies
suggested that the cationic cyclometalated Pd(II) complex
generated by the oxidative addition of aminal to a Pd(0)
species was crucial for this unusual transformation.
alladium-catalyzed Heck reaction has proved to be one of
Pthe most powerful strategies for constructing C−C bonds
and has been widely used for synthesis of organic materials,
natural products, and bioactive compounds.1 In these trans-
formations, the Pd−alkyl species is known to be formed as a
versatile reactive species that could be intercepted with different
substrates, other than β-hydride elimination, for establishing
diverse new transformations.2 In this context, the discovery and
development of new and efficient strategies for intercepting the
active Pd−alkyl species is a key for establishing some new
transformations by using a Heck reaction as a starting point. As
such, various methods, such as trapping by alkenes, alkynes, or
CO insertion3 and oxidative intercepting with strong oxidants,
have already been developed to initiate subsequent more
complex reactions.4 However, most reactions suffer from some
disadvantages, such as the use of a stoichiometric amount of
metallic oxidants, toxic reagents, and harsh reaction conditions.
Herein, we described an alternative approach to intercept the
palladium−alkyl species, which led to a new three-component
reaction to afford amino acetals in the absence of oxidants. Such
a reaction would be particularly valuable for synthesis of amino
aldehydes, which are synthetically versatile compounds for the
construction of important pharmaceuticals, natural products,
and modified proteins.5
Our inspiration for this new transformation stems from the
fact that an electron-rich enol ether, when subjected to a Heck-
type reaction to react with an electrophilic cationic RPdL2
species (A), would give rise to a Pd−alkyl species (B or C) with
a carbocation character (Scheme 1).6 Previous studies suggest
that the polarized cationic species is crucial to give the α-
arylated product with high selectivity. We thought that the
cationic Pd(II) intermediate C might be intercepted by a
nucleophile via an out-sphere style mechanism to form the
intermediate E, which will furnish the difunctionalization
product via further reductive elimination. One of the potential
problems facing the development of this transformation is the
competition between the inner nucleophilic attack by the aryl
moiety (migratory insertion) and the proposed nucleophilic
addition by an outer nucleophile. Because the olefin insertion
into metal−alkyl bonds of complexes containing more
electrophilic metal centers are faster than those with more
electron-rich metal centers,7 it would be expected that the Pd−
alkyl species C generated from an cationic alkylpalladium A
containing a more electron-donating moiety would favor the
desired reaction.
Recently, our research group has demonstrated that aminals
can serve as useful electrophiles undergoing oxidative addition
with Pd(0) to form the unique electrophilic cationic Pd−alkyl
species I (confirmed by X-ray crystallographic analysis).8 The
metal center in the isolated Pd−alkyl complex I is thought to be
comparably more electron-rich due to the attached electron-
donating CH2NR2 moiety. Fascinated and inspired by this
unique feature, we envisioned that the complex I could slow
down the corresponding migratory insertion of enol ether and
form intermediate II, which enabled the subsequent nucleo-
philic addition by an outer nucleophile to form III, and then
reductive elimination yielded the desired product of difunction-
lization. To test the viability of the envisioned strategy, we
started the investigation by exploring the reaction of butyl vinyl
ether (1a) with N,N,N′,N′-tetrabenzylmethanediamine (2a)
and 2-PrOH. Because palladium in combination with Xantphos
has shown to be highly effective for the generation of Pd−alkyl
complex I, we initially focused on exploring conditions using
Received: October 16, 2013
Published: November 20, 2013
© 2013 American Chemical Society
18327
dx.doi.org/10.1021/ja410611b | J. Am. Chem. Soc. 2013, 135, 18327−18330

Journal of the American Chemical Society
Communication
a
this readily available catalyst. The results are summarized in
Table 1. As can be seen, when the reaction was conducted in
Table 2. Scope of Aminals and Alcohols
a
Table 1. Screening of Reaction Conditions
b
entry
[Pd]
Pd(Xantphos)Cl2
solvent
yield (%)
1
2
3
4
5
6
7
8
CH3CN
THF
71
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
Pd(Xantphos)Cl2
PdCl2
74
toluene
dioxane
DCM
75
66
trace
65
DMA
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
trace
trace
72
a
Pd(OAc)2
Reaction conditions: 1a (0.8 mmol), 2 (0.4 mmol), 3 (4.0 mmol),
[Pd] (0.02 mmol), toluene (1.5 mL), 110 °C, 12 h, isolated yield
c
9
Pd2(dba)3/Xantphos
Pd(PPh3)Cl2
b
unless otherwise noted. The ratio of 4e to 4d was determined by 1H
10
11
12
13
14
15
16
17
trace
31
Pd(DPPHex)Cl2
Pd(BINAP)Cl2
Pd(DPPE)Cl2
NMR.
58
50
with this process to afford the desired products in moderate to
good yields (Table 2, entries 6−8). However, relatively lower
yield was obtained for aminal derived from cyclic amine (Table
2, entry 9).
Pd(DPEPhos)Cl2
Pd(DPPF)Cl2
65
66
Pd(Xantphos)(CH3CN)2(OTf)2
−
85
trace
Subsequently, the substrate scope of enol ethers was explored
by employing a variety of different substituted enol ethers
(Table 3). Alkyl vinyl ethers can be smoothly transformed into
the desired products in good to excellent yields (Table 3,
entries 1−6). Particularly, when the long-chain dodecyl vinyl
a
Reaction conditions: 1a (0.8 mmol), 2a (0.4 mmol), 3a (4.0 mmol),
b
[Pd] (0.02 mmol), solvent (1.5 mL), 110 °C, 12 h. Isolated yield.
c
Reaction conditions: Pd2(dba)3 (0.01 mmol), Xantphos (0.02 mmol),
HOTf (0.04 mmol).
a
Table 3. Scope of Enol Ethers
the presence of a catalytic amount of Pd(Xantphos)Cl2 in
CH3CN, the desired difuctionalized product 4a was obtained in
good yield (Table 1, entry 1). Screening of some representative
solvents revealed that the most efficient catalysis was furnished
in toluene, in which the desired product 4a was obtained in
75% yield (Table 1, entry 3). Variation of the phosphine ligands
revealed it to be a key factor. Almost no reaction occurred
when Pd(OAc)2 or PdCl2 served as catalyst. The reaction
performed well with Pd2(dba)3 as the palladium source in the
presence of Xantphos, suggesting that Pd(0) was involved in
the present reaction (Table 1, entries 7−9). When PPh3 was
used in place of Xantphos, the reaction virtually stopped.
Among the phosphine ligands examined here, bidentate
phosphine ligands are effective for this reaction, and Xantphos
gave the best result in affording 4a. As expected, a higher yield
of 4a was gained when the cationic Pd(Xantphos)-
(CH3CN)2(OTf)2 was utilized as catalyst (Table 1, entry 16).
In the absence of Pd catalyst, only a trace amount of desired
product was observed under otherwise identical conditions
(Table 1, entry 17).
After establishing these optimized conditions, we next
investigated the generality of this novel difunctionalization
reaction. First, a series of alcohols were used as nucleophiles in
the present reaction. As shown in Table 2, alcohols including
MeOH, EtOH, and n-BuOH reacted successfully with butyl
vinyl ether 1a and aminal 2a, affording the corresponding
products in good to excellent yields (Table 2, entries 1−4).9
Intriguingly, when the sterically hindered t-BuOH was used as a
substrate, not only the corresponding product 4e but also the
product 4d was detected (Table 2, entry 5). Furthermore,
aminals derived from simple alkylamines were also compatible
a
Reaction conditions: 1 (0.8 mmol), 2a (0.4 mmol), 3 (4.0 mmol),
[Pd] (0.02 mmol), toluene (1.5 mL), 110 °C, 12 h, isolated yield
b
unless otherwise noted. Reaction conditions: [Pd] (0.04 mmol), 24 h.
c
Reaction conditions: 1a (0.8 mmol), 2a (0.4 mmol), [Pd] (0.02
d
mmol), toluene (1.5 mL), 110 °C, 24 h. Reaction conditions: 6 h.
e
1
The dr ratio was determined by H NMR.
18328
dx.doi.org/10.1021/ja410611b | J. Am. Chem. Soc. 2013, 135, 18327−18330

Journal of the American Chemical Society
Communication
ether was subjected to this reaction, a higher yield (91%) could
be obtained (Table 3, entry 2). In addition, nonterminal alkenyl
ethers were also suitable for this process, furnishing the
corresponding products in good results (Table 3, entries 7−9).
Cyclic vinyl ethers such as 2,3-dihydrofuran and 3,4-dihydro-
2H-pyran were also compatible, giving the products 4s and 4t
with 4:1 and 1:1 dr ratios as well as 87% and 81% yields,
respectively (Table 3, entries 10 and 11). The product 4s could
also be obtained in gram scale with identically high yield (see
Supporting Information). Impressively, 4-(vinyloxy)butan-1-ol
gave rise to the corresponding adduct 4u in good yield (Table
3, entry 12). Finally, the reaction can also be conducted with
another electron-rich olefin, N-Boc-2,3-pyrroline,10 giving the
desired product 4v in 72% yield (Table 3, entry 13).
The resulting amino acetals can be readily converted into
useful building blocks via simple functional group trans-
formations. For example, the product 4s could be converted
into hemiacetal 5 by hydrolysis under mild conditions in high
yield. Oxidation of 5 with Jones reagent afforded lactone 6 in
83% yield, which is an important building block for synthesis of
bioactive compounds.11 In addition, reduction of the hemi-
acetal moiety in 5 with NaBH4 produced amino alcohol 7 in a
97% yield.
catalyzed by complex I in toluene-d8 (see Supporting
Information). At the beginning, complex I showed up as two
resonances at 3.59 and 14.05 ppm in the 31P NMR spectra.
After heating up to 110 °C for 10 min, two new signals at 6.87
and 9.15 ppm grew up simultaneously. At the same time, the
HRMS (ESI) analysis of the reaction mixture showed a peak at
m/z 894.2297, which corresponded to the mass of [I-OTf]+.
Another peak at m/z 964.2617 was also detected, correspond-
ing to the mass of [II-OTf]+. After 1 h, the 31P NMR became
messy and the above four signals almost disappeared with the
formation of the desired product 4s, which was detected by GC
1
and H NMR (76% yield). The above results support that the
intermediates I and II (or II′) might be involved in the catalytic
cycle of this transformation.
On the basis of the results described above and our previous
report,8 a possible reaction mechanism of the three
components reaction is exemplified in Figure 1. Initially,
Studies were conducted to gain insight into a possible
mechanism for this unusual process (Scheme 2). When
Scheme 2. Preliminary Mechanistic Studies
Figure 1. Plausible reaction mechanism.
reduction of Pd(II) precatalyst by 2-PrOH gives a catalytically
active Pd(0) species together with a catalytic amount of acid.
Subsequent oxidative addition of aminal 2 to the Pd(0) species
quickly takes place via acid-assisted C−N bond cleavage,
generating the key intermediate I. This electrophilic cationic
Pd−complex I reacts with electron-rich enol ether 1, forming a
new Pd−alkyl intermediate II, which is further attacked by a
nucleophile to give intermediate III. Reductive elimination
from III releases the desired product 4 and regenerates the
active Pd(0) species to complete the catalytic cycle.
In summary, we have developed a novel strategy for
intercepting the Pd−alkyl species generated in the Heck
reaction. As a result, a novel palladium-catalyzed difunctionliza-
tion of enol ethers with alcohols and aminals has been
established. One C−C and one C−O bond are formed in this
transformation, which provides a facile access to amino acetals.
Mechanistic experiments suggest that our present work not
only offers a simple and general method for difunctionalization
of simple enol ethers but also provides fundamentally
important insight into intercepting Heck-type Pd−alkyl species
via nucleophilic addition prior to migratory insertion of alkenes.
Pd(Xantphos)(CH3CN)2(OTf)2 was replaced with HOTf as
the catalyst, the reaction did not occur at all, which indicated
that the Pd catalyst was essential for this process (see
Supporting Information). On the other hand, the reaction
proceeded well when the isolated Pd(Xantphos)(CH2NBn2)-
(OTf) complex I was used as catalyst under the standard
conditions. Moreover, the stoichiometric reaction of complex I
with 2,3-dihydrofuran 1s and 2-PrOH at 110 °C successfully
afforded the desired product 4s in a 54% yield, thus indicating
the plausible intermediacy of complex I in the catalytic cycle of
the present reaction. To get further insights into the catalytic
cycle of the present reaction, 31P NMR and ESI-MS
experiments were conducted to monitor the standard reaction
18329
dx.doi.org/10.1021/ja410611b | J. Am. Chem. Soc. 2013, 135, 18327−18330

Journal of the American Chemical Society
Communication
132, 17471. (s) Kalyani, D.; Satterfield, A. D.; Sanford, M. S. J. Am.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
Chem. Soc. 2010, 132, 8419. (t) Kirchberg, S.; Frohlich, R.; Studer, A.
̈
S
Angew. Chem., Int. Ed. 2010, 49, 6877. (u) Pathak, T. P.; Gligorich, K.
M.; Welm, B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 7870.
(v) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2010,
132, 2856. (w) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem.
Soc. 2010, 132, 1474. (x) Nicolai, S.; Piemontesi, C.; Waser, J. Angew.
Chem., Int. Ed. 2011, 50, 4680. (y) Zhu, R.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2012, 51, 1926.
AUTHOR INFORMATION
Corresponding Author
hmhuang@licp.cas.cn
■
(5) (a) Kleinman, E. F. In Comprehensive Organic Synthesis, Vol. 2;
Heathcock, C. H., Ed.; Pergamon Press: Oxford, U. K., 1991; Chapter
4, p 893. (b) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991. (c) Lait,
S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767.
(6) (a) Hahn, C. Chem.Eur. J. 2004, 10, 5888. (b) Mo, J.; Xu, L.;
Xiao, J. J. Am. Chem. Soc. 2005, 127, 751. (c) Amatore, C.; Godin, B.;
Jutand, A.; Lemaître, F. Chem.Eur. J. 2007, 13, 2002. (d) Amatore,
C.; Godin, B.; Jutand, A.; Lemaître, F. Organometallics 2007, 26, 1757.
(e) Henriksen, S. T.; Norrby, P.-O.; Kaukoranta, P.; Andersson, P. G.
J. Am. Chem. Soc. 2008, 130, 10414. (f) Chen, C.; Luo, S.; Jordan, R. F.
J. Am. Chem. Soc. 2010, 132, 5273. (g) Ruan, J.; Iggo, J. A.; Berru, N.
G.; Xiao, J. J. Am. Chem. Soc. 2010, 132, 16689.
(7) For the leading review on migratory insertion, see (a) Cavell, K.
J. Coord. Chem. Rev. 1996, 155, 209. For selective reports on
migratory insertion, see (b) Mecking, S.; Johnson, L. K.; Wang, L.;
Brookhart, M. J. Am. Chem. Soc. 1998, 120, 888. (c) Tye, J. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 14703. (d) Hanley, P. S.;
Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 15661.
(8) Xie, Y.; Hu, J.; Wang, Y.; Xia, C.; Huang, H. J. Am. Chem. Soc.
2012, 134, 20613.
(9) In the absence of alcohols, the reaction of 1a with 2a afforded
N,N-dibenzyl-3,3-dibutoxypropan-1-amine (4d) in 29% yield, the
alcohol moeity stemmed from 1a via C−O bond cleavage; see
Supporting Information for details.
(10) For recent examples on Heck reaction with this olefin, see
(a) Yang, Z.; Zhou, J. J. Am. Chem. Soc. 2012, 134, 11833. (b) Hu, J.;
Hirao, H.; Li, Y.; Zhou, J. Angew. Chem., Int. Ed. 2013, 52, 8676.
(11) (a) Tanaka, H.; Pan, L.; Ikura, K. 3-Acetyl-n-substituted-3-
aminomethyltetrahydroguran-2-one derivative and process therefor.
Eur. Pat. Appl. 1249448 A1, 2002. (b) Lehmann, J. Arch. Pharm. 1984,
317, 126.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Chinese Academy of
Sciences, the National Natural Science Foundation of China
(21222203, 21172226, and 21133011).
REFERENCES
■
(1) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518. (b) Heck, R. F.;
Nolley, J. P. J. Org. Chem. 1972, 37, 2320. (c) Mizoroki, T.; Mori, K.;
Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. For selected reviews on
the Heck reaction, see: (d) Heck, R. F. Acc. Chem. Res. 1979, 12, 146.
(e) Daves, G. D.; Hallberg, A. Chem. Rev. 1989, 89, 1433.
(f) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
(g) Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101. (h) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
(i) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (j) Oestreich,
M. The Mizoroki-Heck Reaction; Wiley: Chichester, UK. 2009.
(k) Coeffard, V.; Guiry, P. J. Curr. Org. Chem. 2010, 14, 212. (l) Le
Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (m) Ruan, J.; Xiao, J.
Acc. Chem. Res. 2011, 44, 614. (n) Mc Cartney, D.; Guiry, P. J. Chem.
Soc. Rev. 2011, 40, 5122. (o) Sigman, M. S.; Werner, E. W. Acc. Chem.
Res. 2011, 45, 874.
(2) For leading reviews, see (a) Wolfe, J. P. Eur. J. Org. Chem. 2007,
571. (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S.
Chem. Rev. 2007, 107, 5318. (c) Jensen, K. H.; Sigman, M. S. Org.
Biomol. Chem. 2008, 6, 4083. (d) McDonald, R. I.; Liu, G.; Stahl, S. S.
Chem. Rev. 2011, 111, 2981.
(3) For selective examples, see (a) Sugihara, T.; Coperet, C.;
Owczarczyk, Z.; Harring, L. S.; Negishi, E.-i. J. Am. Chem. Soc. 1994,
116, 7923. (b) Schweizer, S.; Song, Z.-Z.; Meyer, F. E.; Parsons, P. J.;
de Meijere, A. Angew. Chem., Int. Ed. 1999, 38, 1452. (c) Tietze, L. F.;
Kahle, K.; Raschke, T. Chem.Eur. J. 2002, 8, 401. (d) Artman, G. D.,
III; Weinreb, S. M. Org. Lett. 2003, 5, 1523. (e) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134 ;
also see references therein.
(4) For recent examples of oxidative difunctionalization of alkenes,
see (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690. (b) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J.
̈
̃
Am. Chem. Soc. 2005, 127, 14586. (c) Schultz, M. J.; Sigman, M. S. J.
Am. Chem. Soc. 2006, 128, 1460. (d) Gligorich, K. M.; Schultz, M. J.;
Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 2794. (e) Liu, G.; Stahl, S.
S. J. Am. Chem. Soc. 2006, 128, 7179. (f) Zhang, Y.; Sigman, M. S. J.
Am. Chem. Soc. 2007, 129, 3076. (g) Gligorich, K. M.; Cummings, S.
A.; Sigmann, M. S. J. Am. Chem. Soc. 2007, 129, 14193. (h) Desai, L.
V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737. (i) Muniz, K.
̃
J. Am. Chem. Soc. 2007, 129, 14542. (j) Michael, F. E.; Sibbald, P. A.;
Cochran, B. M. Org. Lett. 2008, 10, 793. (k) Muniz, K.; Hovelmann, C.
̃
̈
H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (l) Li, Y.; Song, D.;
Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962. (m) Wu, T.; Yin, G.;
Liu, G. J. Am. Chem. Soc. 2009, 131, 16354. (n) Sibbald, P. A.; Michael,
F. E. Org. Lett. 2009, 11, 1147. (o) Urkalan, K. B.; Sigman, M. S.
Angew. Chem., Int. Ed. 2009, 48, 3146. (p) Zhang, A.; Jiang, H.; Chen,
H. J. Am. Chem. Soc. 2009, 131, 3846. (q) Sibbald, P. A.; Rosewall, C.
F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009, 131, 15945.
(r) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc. 2010,
18330
dx.doi.org/10.1021/ja410611b | J. Am. Chem. Soc. 2013, 135, 18327−18330