C-C bond-forming reactions via Pd-mediated decarboxylative α-lmino anion generation

Article abstract of DOI:10.1021/ol071080f

α-lmino anions are generated under neutral reaction conditions via a Pd-mediated decarboxylation of allyl diphenylglycinate imines with concomitant formation of a π-allylpalladium species. The resulting delocalized anion can attack the π-allyl-Pd(ll) spec

Full text of DOI:10.1021/ol071080f

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2879-2882
C−C Bond-Forming Reactions via
Pd-Mediated Decarboxylative
Anion Generation
r-Imino
Andrew A. Yeagley and Jason J. Chruma*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
jjc5p@Virginia.edu
Received May 9, 2007
ABSTRACT
r
-Imino anions are generated under neutral reaction conditions via a Pd-mediated decarboxylation of allyl diphenylglycinate imines with
concomitant formation of a -allylpalladium species. The resulting delocalized anion can attack the -allyl-Pd(II) species or be intercepted by
aldehydes to afford homoallylic amines or protected 1,2-amino alcohols, respectively.
π
π
The R-imino anion (2-azaallyl anion) is a valuable synthon
for the construction of organoamines.1 We were particularly
interested in employing an R-imino anion-based protocol
toward the synthesis of homoallylic amines, which serve as
useful synthetic precursors for aza-heterocycles2 and alka-
loids.3 Such a strategy would run counter to standard
approaches toward homoallylic amines, namely, the addition
of allyl organometallics or allylboranes into activated imines.4
Generation of an R-imino anion typically involves deproto-
nation of the conjugate acid with a strong base. Herein, we
report a “neutral” Pd-mediated decarboxylative method for
generating nucleophilic R-imino anions from allyl diphen-
ylglycinate imines. Alkylation of the resulting R-imino anion
with the corresponding π-allyl-Pd intermediate establishes
the desired homoallylic amine framework. Furthermore, the
R-imino anions can be intercepted by aldehydes prior to
allylation to afford protected 1,2-amino alcohols.
We were inspired by recent observations that under general
acid-base catalysis, diphenylglycine (Dφg) will readily
undergo imine formation with R-ketoacids followed by
concomitant decarboxylation and protonation of the resulting
R-imino anion to afford the corresponding N-(diphenyl-
methylene)amino acids.5 To further explore the potential of
Dφg imines as R-imino anion precursors, we sought to
separate the imine formation and decarboxylation steps. Allyl
esters of Dφg seemed well-suited for this goal, given that
they should not interfere with imine formation and they can
be removed readily with Pd(0) catalysts. Upon Pd-mediated
deallylation and ensuing decarboxylation, the resulting
R-imino anion could then attack the Pd(II)-π-allyl species,
affording homoallylic amines (Scheme 1, 1 f 3 + 4). Shortly
after we initiated these investigations, Burger and Tunge
reported a complimentary method toward homoallylic amines
(1) For recent examples and reviews: (a) Lee, J.-H.; Jeong, B.-S.; Ku,
J.-M.; Jew, S.-s.; Park, H.-g. J. Org. Chem. 2006, 71, 6690. (b) Nakoji,
M.; Kanayama, T.; Okino, T.; Takemoto, Y. J. Org. Chem. 2002, 67, 7418.
(c) O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. (d) Pearson, W. H.
Pure Appl. Chem. 2002, 74, 1339. (e) Pearson, W. H.; Stoy, P. Synlett 2003,
7, 903.
(2) (a) Puentes, C. O.; Kouznetsov, V. J. Heterocycl. Chem. 2002, 39,
595. (b) Chiou, W.-H.; Mizutani, N.; Ojima, I. J. Org. Chem. 2007, 72,
1871. (c) Ramachandran, P. V.; Burghardt, T. E.; Bland-Berry, L. J. Org.
Chem. 2005, 70, 7911. (d) Gille, S.; Ferry, A.; Billard, T.; Langlois, B. R.
J. Org. Chem. 2003, 68, 8932.
(3) (a) Atobe, M.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 2005,
46, 2669. (b) Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879. (c)
Kim, G.; Jung, S.-d.; Lee, E.-j.; Kim, N. J. Org. Chem. 2003, 68, 5395. (d)
Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2, 1847. (e)
Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A.; Virdis,
A. Org. Lett. 2004, 6, 493.
(4) (a) Sugiura, M.; Hirano, K.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 7182. (b) Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 7687. (c) Friestad, G. K.;
Korapala, C. S.; Ding, H. J. Org. Chem. 2006, 71, 281. (d) Pandey, M. K.;
Bisai, A.; Pandey, A.; Singh, V. K. Tetrahedron Lett. 2005, 46, 5039. (e)
Ramachandran, P. V.; Burghardt, T. E. Pure Appl. Chem. 2006, 78, 1397.
(f) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(5) (a) Liu, L.; Zhou, W.; Chruma, J.; Breslow, R. J. Am. Chem. Soc.
2004, 126, 8136. (b) Chruma, J. J.; Liu, L.; Zhou, W.; Breslow, R. Bioorg.
Med. Chem. 2005, 13, 5873.
10.1021/ol071080f CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/20/2007

excellent yield. Amines 8 were not amenable to long-term
storage, but the corresponding acetate salts or Cbz-carbam-
ates 7 can be stored indefinitely at 4 °C.
Scheme 1. Complementary Homoallylic Amine Syntheses
Dφg esters 8 were readily converted to the corresponding
imines 1, typically by condensation with the requisite aryl
or heteroaryl aldehydes (Table 1).10 In the case of 3-pyridi-
Table 1. Generation of Imines 1
employing allyl esters of N-(diphenylmethylene)-R-amino
acids (Scheme 1, 2 f 3 + 4).6 Both strategies should proceed
through the same putative intermediates (Ia or Ib) and thus
afford the same products and product ratios. Employing
imines 2, however, necessitates access to the corresponding
R-amino acids, which may represent a greater synthetic
challenge than the desired products. This requirement is
particularly disadvantageous for obtaining complex R-aryl
or heteroaryl homoallylic amines.3 We therefore focused our
initial studies with allyl diphenylglycinate imines 1 toward
the construction of R-aryl or heteroaryl homoallylic amines.
The required H-Dφg allyl esters 8a and 8b were obtained
in three steps and good overall yield on a multigram scale
(Scheme 2). Cbz protection of commercially available Dφg
Scheme 2. Synthesis of Dφg Esters 8
a Conditions: A ) 8 + aldehyde (1 equiv), PhH, reflux (Dean-Starke),
24 h; B ) 8 + imine (1 equiv), CH2Cl2, 4 Å MS, 23 °C, 24 h; C ) 8 +
ethyl glyoxylate (∼1 equiv), PhCH3, 4 Å MS, 23 °C, 24 h. bOnly performed
once.
necarboxaldehyde, however, heating with amine 8a in
benzene at reflux resulted in imine formation followed
unexpectedly by deallylation, decarboxylation, and proto-
nation to afford benzophenone imine 9 in 92% yield. To
circumvent this problem, amine 8a was stirred with 3-py-
ridinecarboximine at room temperature overnight. Under
these milder conditions, transimination proceeded without
concomitant decarboxylation, affording imine 1h in good
yield. Imines 1 were purified by flash chromatography using
ethyl acetate and hexanes buffered with 1-2% Et3N as
eluent. The noncrystalline electron-rich aldimines (e.g., 1g)
exhibited increased sensitivity toward hydrolysis during
chromatography, thus accounting for the corresponding
modest isolated yields.
(5) proceeded in 84% isolated yield,7,8 and the resulting
carboxylic acid 6 was allylated with allyl bromide or
2-methylallyl bromide to afford esters 7a and 7b, respec-
tively. Although the allylation reactions proceeded in modest
yield, the remainder of the mass balance was unreacted acid
6, which was readily recovered by flash chromatography and
resubjected to the reaction conditions. Selective deprotection
of the Cbz-carbamate over the allyl ester was performed
using iodotrimethylsilane,9 providing amines 8a or 8b in
(6) Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002.
(7) Crisma, M.; Valle, G.; Bonora, G. M.; De Menego, E.; Toniolo, C.;
Lelj, F.; Barone, V.; Fraternali, F. Biopolymers 1990, 30, 1.
(8) Unless otherwise noted, all reported yields represent average isolated
yields for at least two runs.
Initial reaction optimization studies were performed on
benzaldimine 1a (Table 2). The ratio of regioisomeric
(9) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. J. Chem. Soc., Chem.
Commun. 1979, 11, 495.
(10) Though considerably more sensitive to hydrolysis, imines 1 can also
be derived from aliphatic aldehydes (e.g., isobutyraldehyde).
2880
Org. Lett., Vol. 9, No. 15, 2007

Table 2. Solvent and Catalyst Effects
Table 3. Pd-Mediated Decarboxylative Allylations
isolated ratio
solvent
catalyst
time
1 h
15 minb 92%
25 min 94%d
40 min 83%d
30 min 96%
1 h
15 min 89%d
-
-
yield (3a/4a)
toluenea 15% Pd(dba)2, 15% dppf
THF-d8 10% Pd(dba)2, 10% dppf
CH2Cl2 10% Pd(dba)2, 10% dppf
dioxane 10% Pd(dba)2, 10% dppf
MeCN
THF
MeCN
MeCN
MeCN
82%
2.6:1
3.8:1
5.2:1
5.5:1
6.1:1
2.5:1
4.5:1
-
10% Pd(dba)2, 10% dppf
10% Pd(dba)2, 10% dppe
10% Pd(dba)2, 20% PPh3
5% (PdC3H5Cl)2, 10% dppfc
10% Pd(OAc)2
79%d
0%
0%
-
a Required continuous bubbling of Ar through the reaction mixture.
c
bMonitored by 1H NMR spectroscopy. NaOAc added. dOnly performed
once.
products 3a and 4a was determined by 1H NMR analysis of
the unpurified reaction mixture. Employing a Et3N-buffered
eluent, 3a and 4a were purified from the reaction mixture
by flash chromatography, though they coeluted; the corre-
sponding 1H NMR spectra typically provided a product ratio
similar to the unpurified reaction mixture. Subjection of the
mixture of imine products to nonbuffered silica gel resulted
in preferential hydrolysis of aldimine 4a, allowing for
exclusive isolation of the desired N-(diphenylmethylene)-
imine 3a in spectroscopically pure form. This behavior was
general for all compounds tested.
Solvent appears to play only a minor role in regards to
isolated yield and product ratio. In most solvents studied,
using 10 mol % of Pd(dba)2 and 10 mol % of diphenylphos-
phinoferrocene (dppf) at 23 °C, imine 1a was converted to
homoallylic amines 3a and 4a in excellent yield and a ∼5:1
ratio, respectively. Acetonitrile (MeCN) afforded the best
yields and product ratios. Toluene, however, was an excep-
tion, in that reaction rates were slow; the product ratio was
relatively low; and great care had to be taken to degas the
solvent to prevent precipitation of the catalyst. Modification
of the palladium source or ligands did not favorably impact
yield or product ratio. The ligand diphenylphosphinoethane
(dppe) in THF11 proved inferior to dppf in MeCN in all
regards. Likewise, use of triphenylphosphine (PPh3) as the
ligand accelerated the reaction rate but decreased the yield
and product ratio. Interestingly, Pd(II) catalysts, including
the π-allyl palladium dimer (PdC3H3Cl)2, did not effect the
desired reaction.
a Determined by 1H NMR spectroscopy of the unpurified reaction
mixture. bImine 9 isolated in ca. 50% yield. cReaction heated to 40 °C.
dOnly performed once.
3 and 4 in nearly quantitative yield. The electron-rich
aldimines (i.e., 4d-g), however, were particularly sensitive
toward hydrolysis during chromatography, even under Et3N-
buffered conditions, resulting in lowered isolated yields for
3 + 4. Electron-donating substituents also decreased the
reaction rate and reduced the ratio of homoallylic imines
3/4.12 Alternatively, electron-withdrawing groups that can
shift the electron density in the intermediate R-imino anion
toward the substituent via delocalization (e.g., 4-cyanoben-
zaldimine 1c or ethyl glyoximine 1i) increased the reaction
rate and afforded the N-(diphenylmethylene)imine 3 as
essentially the sole product (g20:1 product ratio) in excellent
yield.
Electronegative substituents that cannot further delocalize
the negative charge in the intermediate R-imino anion (e.g.,
p-fluorobenzaldimine 1b) did not dramatically impact the
reaction profile in comparison to benzaldimine 1a. An
apparent exception to these trends is 3-pyridylcarboximine
1h, in which the benzophenone imine 3h was the sole
homoallylic imine product, though it was isolated in only
47% yield. The remaining mass balance was imine 9,
suggesting that protonation of the intermediate R-imino anion
competes with allylation. The strong preference for product
3h was surprising, given that the 3-pyridyl substituent has
Imines 1b-j were also converted to the corresponding
homoallylic amines 3 and 4 under our optimized reaction
conditions (Table 3). The electronic character of the imine
proved to have a significant impact on the reaction rate, yield,
and product ratio. Except for imine 1h, all imines were
converted to the corresponding mixture of homoallylic imines
(12) O2 must be excluded from the reaction mixture with imines 1e-g
to prevent precipitation of an organometallic species, presumably arising
from imine-directed electrophilic addition of Pd(II) into the electron-rich
aromatic rings: Ryabov, A. D. Synthesis 1985, 233.
(11) Poor solubility of the Pd-dppe complex in MeCN resulted in no
conversion in that solvent.
Org. Lett., Vol. 9, No. 15, 2007
2881

an electronic profile similar to phenyl (i.e., 1a). Protonation
of the pyridine nitrogen is expected to shift the electron
density of the intermediate anion to favor production of 3h
over 4h as well as to provide an acidic proton source leading
to methylene amine 9; DFT calculations support this
hypothesis (see Supporting Information). Alternatively,
coordination of the pyridine nitrogen to the Pd(II) intermedi-
ate would have a similar effect on the electron density of
the anion, but this would not account for the production of
the conjugate acid 9. The source of the acidic proton is
currently under investigation.
Substituents on the 2-position of the allyl ester also
favorably impact the product ratio (3:4). 2-Methylallyl ester
1j was readily converted to the homoallylic imine 3j as the
sole product in good yield, though the reaction required
gentle heating (40 °C). The requirement for elevated reaction
temperatures is most likely a result of the higher activation
energy required for initial complexation of the Pd(0) catalyst
to the less accessible 2-methylallyl substituent.13,14
and diastereomeric ratios. Production of diastereomers 10
most likely results from interception of the R-imino anion
intermediate by unreacted benzaldehyde, followed by ally-
lation of the resulting alkoxide, thus representing a Pd-
mediated decarboxylative variant of the Erlenmeyer reac-
tion.15 Increasing the amine/aldehyde mixing time did not
dramatically reduce formation of amino alcohol 10.
This intriguing reaction pathway can predominate over
homoallylic amine synthesis if more electrophilic aldehydes
are employed. Specifically, treatment of benzaldimine 1a
with 10 mol % of Pd(dba)2/dppf in the presence of p-
cyanobenzaldehyde (2 equiv) afforded the allyl ether 11a in
53% isolated yield as an inseparable mixture of diastereomers
(Scheme 4). The remaining mass balance was the 1,2-imino
Scheme 4. Interception of the R-Imino Anion
We also investigated combining imine formation and Pd-
mediated decarboxylative allylation into one reaction vessel.
Our initial attempt at a “one-pot” protocol involved premix-
ing amine 8a with benzaldehyde in MeCN (5 min), followed
by addition of catalytic Pd(0) (Scheme 3). In addition to the
alcohol 11b, presumably arising from protonation of the
intermediate alkoxide with adventitious water. Importantly,
only trace amounts (e5%) of homoallylic amine products
were observed. Optimization of this novel reaction manifold
is the subject of current investigation.
Scheme 3. Attempted “One-Pot” Reaction
In summary, we report the mild conversion of allyl
diphenylglycinate imines into R-aryl and heteroaryl homo-
allylic amines employing a Pd-mediated decarboxylative
generation and allylation of R-imino anions. The intermediate
anions can be intercepted with aldehydes to afford protected
1,2-amino alcohols. Further investigations will focus on
developing asymmetric variants of these efficient C-C bond-
forming events.
expected homoallylic amine products 3a and 4a, a diaster-
eomeric mixture of allyl ethers 10a and 10b was observed
(as determined by H NMR spectroscopy and HPLC/MS).
1
Unfortunately, the protected 1,2-amino alcohols 10a and 10b
coeluted with 3a, and H NMR analysis of the unpurified
reaction mixture was not sufficient for determining product
Acknowledgment. Financial support was provided by the
U.Va. Dept. of Chemistry and the U.Va. Institute on Aging.
DFT calculations were performed by Prof. Carl O. Trindle
(U.Va.). We thank Prof. Karl Scheidt (Northwestern U.) for
an inspiring conversation.
1
(13) Tsuda, T.; Chujo, Y.; Nishi, S.-i.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6381.
(14) Subjection of crotyl ester 1k to our reaction conditions resulted in
a complex mixture of inseparable products 12a, 12b, and 13.
Supporting Information Available: Experimental pro-
cedures, characterization data, and DFT calculations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL071080F
(15) Erlenmeyer, E., Jr. Annalen 1899, 307, 70.
2882
Org. Lett., Vol. 9, No. 15, 2007