Aminative umpolung of aldehydes to α-amino anion equivalents for pd-catalyzed allylation: An efficient synthesis of homoallylic amines

Article abstract of DOI:10.1021/ol4034012

An attractive strategy for generation of α-amino anions from aldehydes with applications in synthesis of homoallylic amines is described. Aromatic aldehydes can be converted to α-amino anion equivalents via amination with 2,2-diphenylglycine and subsequen

Full text of DOI:10.1021/ol4034012

Letter
pubs.acs.org/OrgLett
Aminative Umpolung of Aldehydes to α‑Amino Anion Equivalents
for Pd-Catalyzed Allylation: An Efficient Synthesis of Homoallylic
Amines
Lei Ding, Jing Chen, Yifan Hu, Juan Xu, Xing Gong, Dongfang Xu, Baoguo Zhao,* and Hexing Li
The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Lab of Rare Earth Functional Materials, Shanghai Normal
University, Shanghai 200234, China
S
* Supporting Information
ABSTRACT: An attractive strategy for generation of α-amino anions from
aldehydes with applications in synthesis of homoallylic amines is described.
Aromatic aldehydes can be converted to α-amino anion equivalents via
amination with 2,2-diphenylglycine and subsequent decarboxylation. The in
situ generated α-imino anions are highly reactive for Pd-catalyzed allylation,
forming the corresponding homoallylic amines in high yields with excellent
regioselectivity.
Scheme 1. α-Amino Anion Routes for the Synthesis of
Homoallylic Amines
omoallylic amines are important compounds and have
Hserved as valuable precursors for the synthesis of a variety
of heterocycles, natural products, and pharmaceutical com-
pounds.1 Its synthesis has attracted much attention.1,2 Tradi-
tional synthetic routes to homoallylic amines have relied on the
addition of nucleophilic allylic organometallics to imines.1,2
Conversely, addition of α-amino anions to electrophilic allylic
cations has afforded a complementary approach. However, it is
not easy to obtain α-amino anion equivalents directly from
amines.3 Since the past decade, decarboxylative alkylation4,5 has
been developed into one of the most powerful synthetic
methodology by Stoltz,6 Tunge,7 Trost,8 and others.9,10
Application of this reaction into amino acid allylic esters has
resulted in an interesting protocol to construct homoallylic
amines via connecting α-amino anions to allylic cations.11,12 By
using this strategy elegantly, Tunge11 developed a Pd-catalyzed
decarboxylative coupling of allylic esters of N-(diphenyl-
methylene)-α-amino acids in 2006 (Scheme 1a), and
Chruma12a also reported a Pd-catalyzed decarboxylative
alkylation of allyl diphenylglycinate imines in 2007 (Scheme
1b). Both of the reactions were proposed to be initiated by
oxidative addition of the allyl ester to Pd catalyst, followed by in
situ generation of an α-imino anion and a Pd(II)−π-allyl
moiety, which underwent further reaction to give the
homoallylic amines.
Given the ready availability of aldehyde feedstocks,
generation of nucleophilic α-amino anions directly from
aldehydes would be particularly appealing. Further reaction of
these α-amino anions with electrophiles, e.g., Pd(II)−π-allyl
species, can provide an efficient access to various amines
(including homoallylic amines Scheme 1c). We envisioned that
the metal carboxylate salt of 2,2-diphenylglycine imine (6),
which could be obtained from aldehyde (1) by condensation
with 2,2-diphenylglycine (2), might undergo decarboxylation to
generate a resonance-delocalized 2-azaallylanion 7 (Scheme
2).11,12 The 2-azaallylanion 7 attacks an allylic electrophile to
give homoallylic imines 4 and 5. The desired N-diphenylketi-
mine 4 can be formed predominantly in the reaction owing to
steric preference and conjugation effect. In this scenario, the
diphenylglycine not only provides the amino group but also
umpolungs the reactivity of the aldehyde in the trans-
Received: November 23, 2013
Published: January 17, 2014
© 2014 American Chemical Society
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Letter
Scheme 2. Strategy for the Synthesis of Homoallylic Amines
from Aldehydes
Table 1. Optimization Studies on the Reaction of Schiff Base
Lithium Salt 6a and Allylic Electrophile 3
a
formation.13 Treatment of the amination product 4 with HCl at
room temperature would give the primary homoallylic amine 8
and cogenerate benzophenone (9). Herein, we wish to report
the preliminary results on this project.
Studies started with the synthesis of the lithium salt of
diphenylglycinate imine 6a, obtained in high yield via
condensation of benzaldehyde and 2,2-diphenylglycine (2) in
the presence of lithium tert-butoxide (LiO-t-Bu) (Scheme 3).
Scheme 3. Synthesis of Lithium Salt 6a
a
Lithium salt 6a is a white solid that is relatively stable in the
solid state and can be handled without special caution to
moisture and oxygen; however, it undergoes decarboxylation in
aprotic solvent such as THF. When NaO-t-Bu or KO-t-Bu was
used instead of LiO-t-Bu, the condensation was a little messy as
All reactions were carried out with 6a (0.24 mmol), 3 (0.20 mmol),
[Pd] (0.010 mmol, 5 mol %), and ligand (0.012 mmol for bidentate
ligand and 0.024 mmol for PBu3) in dry THF (0.50 mL) at room
b
temperature. Conversion was based on 3 and determined by 1H
c
NMR analysis of the crude reaction mixture. The ratio of 4 to 5 was
determined by H NMR analysis of the crude reaction mixture. The
value in parentheses is the isolated yield based on 3.
d
1
1
judged by H NMR analysis of the crude reaction mixture.
Without base, the corresponding Schiff base was hardly
observed in the reaction of benzaldehyde and diphenylglycine.
With lithium salt 6a in hand, we then investigated its reaction
with allylic electrophiles 3 using a Pd−phosphine complex as
the catalyst (Table 1). In the presence of 2.5 mol % of
Pd2(dba)3−dppb, the reaction of 6a and allyl acetate (3a)
proceeded smoothly under room temperature to afford the
product in excellent substrate conversion with a high
regioselectivity for the desired N-diphenylketimine 4a (entry
1). The Pd catalyst is important for the reaction in terms of
reactivity and regioselectivity (entries 1−11). Further opti-
mization showed that Pd2(dba)3−dppe was optimal catalyst,
and THF was the choice of solvent (entry 6). The leaving
group of the allylic electrophile was also examined by using 2-
phenyl allyl alcohol derivatives 3b1−b4 as the substrate (entries
12−15). Although all of the substrates exhibited high reactivity
and excellent regioselectivity, allyl carbonates 3b3 and 3b4 gave
better isolated yields; thus, we chose allyl methyl carbonates as
substrates in the following studies.
Under the optimized conditions, allyl methyl carbonates 3
were screened for allylation by using the preprepared lithium
salt 6a as the α-amino anion precursor (Table 2). In the
presence of Pd catalyst, various alkyl- and aryl-substituted allyl
methyl carbonates reacted efficiently with 6a to give the desired
N-diphenylketimines 4 in high yields with excellent regiose-
lectivity. Functional groups such as C−C double bond, acetal,
and Br are well tolerated by the reaction (Table 2, entries 4, 6,
and 8). Substrates with electron-withdrawing groups have lower
regioisomeric ratios of 4 to 5 (Table 2, entries 8 and 17).
Substituted allyl methyl carbonates 3b3−3t exhibited higher
selectivity for 4 over 5 than allyl acetate (3a) (entries 2−20 vs
1), indicating that steric hindrance has a favorable effect on the
formation of diphenyl ketimines 4.
As shown in Scheme 3, Schiff base lithium salts can be readily
obtained from aldehydes by stirring with 2,2-diphenylglycine
(2). The simple manipulation provides opportunity to develop
a one-pot procedure for the synthesis of homoallylic imines 4
directly from aldehydes. For example, condensation of
benzaldehyde with 2 in methanol at room temperature,
followed by solvent removal and Pd-catalyzed allylation with
methyl 2-methylallyl carbonate (3c) in dry THF, gave the
corresponding homoallylic imines in 85% yield with a ≥20:1
ratio of 4c to 5c (Table 3, entry 1). The yield and
regioselectivity are similar to those obtained from the reaction
using the preprepared lithium salt 6a (Table 2, entry 2).
Following the one-pot procedure, various aromatic aldehydes
were examined in the allylation with allyl methyl carbonates
3b3 and 3c (Table 3). Substituted benzaldehydes (entries 2−8
and 10−14), 2-naphthyl aldehyde (entry 9), and heteroar-
omatic aldehydes (entries 15−16) were all highly effective for
the reaction, providing various homoallylic imines in high
yields. In all these cases, the desired ketimines 4 were formed
predominantly. Electron-deficient aldehydes exhibited higher
regioselectivity for 4 over 5 than electron-rich ones (Entries 4,
10, 12, and 14 vs 6−7 and 13), probably due to electron-
withdrawing group shifting the electron density toward the
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Letter
a
Table 2. Pd-Catalyzed Allylation of Allyl Methyl Carbonates
3 with Schiff Base Lithium Salt 6a
Table 3. One-Pot Synthesis of Homoallylic Imines
a
a
All reactions were carried out with 1 (0.48 mmol), 2 (0.48 mmol), 3
Å molecular sieve (100 mg), LiO-t-Bu (0.48 mmol), 3 (0.40 mmol),
Pd2(dba)3 (0.010 mmol), and dppe (0.024 mmol) at room
temperature unless otherwise stated. For entries 10 and 14, 1 (0.44
mmol), 2 (0.44 mmol), and LiO-t-Bu (0.44 mmol) were used.
a
All reactions were carried out with 6a (0.22 mmol), 3 (0.20 mmol),
b
c
Isolated yield based on 3. The ratio of 4 to 5 was determined by 1H
Pd2(dba)3 (0.0050 mmol), and dppe (0.012 mmol) in dry THF (0.50
NMR analysis of the crude reaction mixture.
mL) at rt overnight unless otherwise stated. For entries 1−2 and 4−5,
b
c
6a (0.24 mmol) was used. Isolated yield based on 3. The ratio of 4
to 5 was determined by 1H NMR analysis of the crude reaction
mixture.
Scheme 4. Synthetic Transformation of Homoallylic Imines
carbon center adjacent to the aryl group in the delocalized 2-
azaallyl anion 7 (Scheme 2) and thus favoring the formation of
ketimine product. However, aliphatic aldehydes such as
butyraldehyde are ineffective for this transformation under
the current conditions.
The resulting homoallylic imines 4 can be utilized to
synthesize various nitrogen-containing compounds. For exam-
ple, primary homoallylic amine 10 could be obtained in 95%
yield from ketimine 4h by deprotection with HCl, which was
further converted to bioactive tetrahydroquinoline14 11 in 91%
yield via intramolecular coupling (Scheme 4). Eight-membered
cyclic amine 12 also could be conveniently prepared in 77%
total yield in four steps from ketimine 4f (Scheme 4).
Although a precise mechanism awaits further studies, we have
compared the allylation of lithium salt 6a with 3b3 and
Chruma’s reaction of the correponding allyl diphenylglycinate
imine (Scheme 1b)12a via 1H NMR spectroscopic studies
(Supporting Information). The current allylation was much
slower than Chruma’s reaction under similar conditions. In
monitoring the reaction of 6a and 3b3, we did not observe any
signals asigned to Chruma’s reactant, which could be generated
if the reaction first undergoes allylic substitution to form an allyl
diphenylglycinate imine and then follows Chruma’s sequence.
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Letter
3109. (c) Trost, B. M.; Lehr, K.; Michaelis, D. J.; Xu, J.; Buckl, A. K. J.
Am. Chem. Soc. 2010, 132, 8915.
In summary, we have demonstrated an attractive strategy to
convert aldehydes to α-amino anions by using 2,2-diphenyl-
glycine as an amination−Umpolung reagent. The in situ
generated α-imino anions 7 are highly reactive for Pd-catalyzed
allylation to give various homoallylic imines 4 in high yields
with excellent regioselectivity. The transformation employs two
readily available electrophiles (aldehydes and allylic electro-
philes) as the starting materials to make the homoallylic amines
and can be carried out under very mild conditions, providing a
nontraditional, versatile, and complementary method for the
synthesis of homoallylic amines. Further studies on mecha-
nisms and development of an asymmetric process are currently
underway.
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ASSOCIATED CONTENT
* Supporting Information
Procedures for the allylation and the synthesis of compounds
6a and 10−13 and characterization data along with NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhaobg2006@shnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Program of Professor of
Special Appointment (Eastern Scholar) at the Shanghai
Institutions of Higher Learning, NSFC (21272158), NCET
(NCET-12-1054), PCSIRT (IRT1269), and Shanghai Govern-
ment projects (12ZR1421900, 13YZ055, 12PJ1406900).
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