Preparation of α-imino aldehydes by [1,3]-rearrangements of O-alkenyl oximes

Article abstract of DOI:10.1021/ol402237w

The synthesis of α-imino aldehydes has been achieved through the thermal [1,3]-rearrangement of O-alkenyl benzophenone oximes. A copper-mediated C-O bond coupling between benzophenone oxime and alkenyl boronic acids provides facile access to the required O-alkenyl oximes and a Horner-Wadsworth-Emmons olefination can be applied to the α-imino aldehyde products to give γ-imino-α,β-unsaturated esters. The scope of the method is described and mechanistic experiments are discussed.

Full text of DOI:10.1021/ol402237w

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Preparation of r‑Imino Aldehydes by
[1,3]-Rearrangements of O‑Alkenyl Oximes
Dimitra Kontokosta, Daniel S. Mueller, Heng-Yen Wang, and Laura L. Anderson*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607, United States
lauralin@uic.edu
Received August 6, 2013
ABSTRACT
The synthesis of r-imino aldehydes has been achieved through the thermal [1,3]-rearrangement of O-alkenyl benzophenone oximes. A copper-
mediated CÀO bond coupling between benzophenone oxime and alkenyl boronic acids provides facile access to the required O-alkenyl oximes
and a HornerÀWadsworthÀEmmons olefination can be applied to the r-imino aldehyde products to give γ-imino-r,β-unsaturated esters.
The scope of the method is described and mechanistic experiments are discussed.
R-Amino aldehydes are versatile intermediates in organic
synthesis. These compounds undergo reductions and nu-
cleophilic additions to form stereodefined amino alcohols,
are converted to allylic amines or R,β-unsaturated γ-amino
esters with olefination reagents, and act as dienophiles
for hetero-DielsÀAlder reactions.1 Traditional methods
for the preparation of R-amino aldehydes involve either
the reduction of R-amino acid derivatives or the oxidation
of 1,2-amino alcohols.2 Enamine catalysis has also recently
been shown to be highly effective for the R-amination of
aldehydes with diazodicarboxylates (Scheme 1).3 In con-
trast to these established methods, we wondered if R-amino
aldehydes could be accessed from alkenyl boronic acids.
This approach would effectively bypass the need for an
aldehyde or carboxylic acid derivative and allow prepara-
tion of R-amino aldehydes from terminal alkynes through
simple hydroboration.4
Recently, we discovered that acetophenone-derived
O-alkenyl oximes undergo a [1,3]-rearrangement and cy-
clization sequence to form 2,3,5-trisubstituted pyrroles
through an R-imino aldehyde intermediate.5,6 We specu-
lated that the use of a nonenolizable oxime under similar
reaction conditions would prevent pyrrole formation and
facilitate the development of alternative synthetic applica-
tions for this unique route to these reactive species. Herein
we describe a procedure for the preparation of R-imino
aldehydes from alkenyl boronic acids through a two-step
sequence involving CÀO bond coupling with benzophenone
oxime followed by a [1,3]-rearrangement of the resulting
O-alkenyl oxime ether (Scheme 1). A subsequent HornerÀ
WadsworthÀEmmons (HWE) olefination has also been
used to demonstrate the synthetic utility of the rearrange-
ment-generated R-imino aldehydes for the preparation of
γ-imino-R,β-unsaturated esters, and appropriate hydrolysis
conditions have been determined to afford access to the
(1) For reviews on the preparation and synthetic applications of
R-amino aldehydes, see: (a) Hili, R.; Baktharaman, S.; Yudin, A. K. Eur.
J. Org. Chem. 2008, 5201. (b) Baktharaman, S.; Hili, R.; Yudin, A. K.
Aldrichimica Acta 2008, 41, 109. (c) Gryko, D.; Chalko, J.; Jurcazk, J.
Chirality 2003, 15, 514. (d) Jurczak, J.; Golebiowski, A. Chem. Rev.
1989, 89, 149.
(2) For examples of R-amino aldehyde preparation by the reduction
of R-amino acid derivatives and the oxidation of amino alcohols, see: (a)
Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org. Chem.
1999, 64, 8962. (b) Dai, C.; Stephenson, C. R. J. Org. Lett. 2010, 12, 3453.
(c) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman,
B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359. (d) Jurczak, J.; Gryko,
D.; Kobrzycka, E.; Gruza, H.; Prokopowicz, P. Tetrahedron 1998, 54,
6051. (e) Leonori, D.; Seeberger, P. H. Org. Lett. 2012, 14, 4954.
(3) For the use of enamine catalysis for the R-amination of aldehydes,
see: (a) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975. (b) Janey,
J. M. Angew. Chem., Int. Ed. 2005, 44, 4292. (c) Erdik, E. Tetrahedron
2004, 60, 8747. (d) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.;
Zhuang, W.; Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790.
(e) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (f) Greck, C.; Drouillat,
B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 1377.
(4) For the preparation of alkenyl boronic acids from alkynes, see:
Brown, H. C.; Campbell, J. B. J. Org. Chem. 1980, 45, 389.
(5) (a) Wang, H.-Y.; Mueller, D. S.; Sachwani, R. M.; Kapadia, R.;
Londino, H. N.; Anderson, L. L. J. Org. Chem. 2011, 76, 3203. (b) Wang,
H.-Y.; Mueller, D. S.; Sachwani, R. M.; Londino, H. N.; Anderson,
L. L. Org. Lett. 2010, 12, 2290.
(6) For an example of a [1,3]-rearrangement of an aryl ether of
N-hydroxyphthalimide, see: Kikugawa, Y.; Tsuji, C.; Miyazawa, E.;
Sakamoto, T. Tetrahedron Lett. 2001, 42, 2337.
r
10.1021/ol402237w
XXXX American Chemical Society

corresponding free amine.7,8 This new method provides an
alternative route for the preparation of R-amino aldehydes
from alkenyl boronic acids that bypasses the need for a
carbonyl functionalized precursor.
Table 1. Optimization of Cu-Mediated Oxime Ether Synthesis
Scheme 1. Synthesis of R-Amino Aldehydes
entry
R
Cu salt
base
Py
additive
3b (yield, %)
1
Me
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl
none
3a (18)
3a (12)
3a (28)
3a (32)
3a (29)
3a (nr)
3a (51)
3b (62)
3b (58)
3b (7)
2
Me
NEt3
none
3
Me
DMAP
none
4
Me
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
none
5
Me
none
6
Me
Cu(acac)2
CuTC
none
7
Me
none
8
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
CuTC
AgBF4
AgOTf
none
9
CuTC
10
11
12
13
CuOTf c
CuTC
AgClO4
3b (70)
3b (39)
3b (90)
d
CuTC
CuTCc
AgClO4
e
AgClO4
a Reaction mixtures were prepared as 1:2:1:3:4:0.5 mixtures of
1/2/[Cu]/base/Na2SO4/additive in DCE (0.1 M). b Percent yield determined
1
by H NMR spectroscopy using CH2Br2 as a reference. c [CuOTf]2 Tol.
3
d 0.2 equiv of AgClO4 was used. e A second portion of 2b was added after
1.5 h. TC = 2-thiophenecarboxylate.
The O-alkenyl oximes required for the targeted [1,3]-
rearrangement were prepared by a ChanÀLamÀEvans
CÀO bond coupling between benzophenone oxime 1 and
alkenyl boronic acids 2.9,10 Propenyl oxime ether 3a was
first isolated from a Cu(OAc)2-mediated reaction mixture,
albeit in low yield due to competing hydrolysis of 1(Table1,
entry 1). Preliminary optimization of this transformation
included a survey of copper salts and amine bases which
identified CuTC as the most effective coupling reagent and
DABCO as the best choice of base (Table 1, entries 2À7).
Surprisingly, the addition of silver salts to the coupling
reaction mixture of 1 and 1-hexenylboronic acid 2b had a
dramatic effect on the yield of 3b. The influence of these
additives was highly dependent on the choice of counterion,
but a control experiment suggested that the silver salts were
not simply acting as counterion exchange reagents and
AgOTf was ineffective in the absence of CuTC (Table 1,
entries 8À11). AgClO4 was identified as the best source of
Ag(I) and was most effective when used at 50 mol %
loading. Further tuning of the reaction conditions ulti-
mately showed that addition of a second portion of 2 equiv
of boronic acid 2b after 1.5 h provided the highest yields of
O-alkenyl oxime 3b (Table 1, entry 13).11 These optimal
conditions were then used to explore the scope of the oxime
ether synthesis.
A variety of trans-alkenylboronic acids undergo copper-
mediated CÀO bond coupling to form O-alkenyl benzo-
phenone oximes 3. As shown in Table 2, several alkenyl-
boronic acids with linear and branched alkyl substituents
were well-tolerated, including a bulky tert-butyl group
and an R-substituted benzyl functionality (entries 1À9).12
Cyclopropylvinylboronic acid 2i was tested and provided
the corresponding oxime ether 3i without any evidence of
ring-opened side products.13 Alkenylboronic acids with
both silyl- and benzyl-protected alcohol substituents also
gave the desired alkenyl benzophenone oximes in high yields
when the ether was one or more methylene units away from
the olefin (Table 2, entries 10 and 11). We were pleased to
discover that chloro-, ester-, and cyano-substituted alkenyl-
boronic acids were similarly tolerant of the copper-mediated
reaction conditions since these functionalities provide
(7) For examples of the trapping of R-amino aldehyde intermediates
with HWE reagents, see: (a) Kotkar, S. P.; Chavan, V. B.; Sudalai, A.
Org. Lett. 2007, 9, 1001. (b) Simmons, B.; Walji, A. M.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2009, 48, 4349. (c) Jha, V.; Kondekar,
N. B.; Kumar, P. Org. Lett. 2010, 12, 2762. (d) Soto-Cairoli, B.; De
Pornar, J. J.; Soderquist, J. A. Org. Lett. 2008, 10, 333 and ref 2b.
(8) For references on vinylogous amino acids, see: (a) Hagihara, M.;
Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem.
Soc. 1992, 114, 6568. (b) Hagihara, M.; Anthony, N. J.; Stout, T. J.;
Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 6570. (c) Mali,
S. M.; Bandyopadhyay, A.; Jadhav, S. V.; Kumar, M. G.; Gopi, H. N.
Org. Biomol. Chem. 2011, 9, 6566 and references within.
(9) For reviews and examples of O-alkenylation with boronic acids,
see: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav,
P. K. Tetrahedron Lett. 2001, 42, 3415. (b) Lam, P. Y. S.; Vincent, G.;
Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44, 4927. (c) Qiao, J. X.;
Lam, P. Y. S. Synthesis 2011, 829. (d) Quach, T. D.; Batey, R. A. Org.
Lett. 2003, 5, 1381. (e) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic,
C. A. J. Am. Chem. Soc. 2010, 132, 1202. (f) Winternheimer, D. J.;
Merlic, C. A. Org. Lett. 2010, 12, 2508. (g) Chan, D. G.; Winternheimer,
D. J.; Merlic, C. A. Org. Lett. 2011, 13, 2778. (h) Winternheimer, D. J.;
Shade, R. E.; Merlic, C. A. Synthesis 2010, 2497. (i) Patil, A. S.; Mo,
D.-L.; Wang, H.-Y.; Mueller, D. S.; Anderson, L. L. Angew. Chem., Int.
Ed. 2012, 51, 7799.
(11) Initial addition of 4 equiv of 2b was less efficient.
(12) Styrenyl boronic acids gave primarily homocoupling products.
(13) (a) Kim, S.; Yoon, J.-Y., Novel Radical Traps. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001. (b) Newcomb, M. Tetrahedron 1993, 49, 1151. (c) Halgren, T. A.;
Roberts, J. D.; Horner, J. H.; Martinez, F. N.; Tronche, C.; Newcomb,
M. J. Am. Chem. Soc. 2000, 122, 2988. (d) Newcomb, M.; Chestney,
D. L. J. Am. Chem. Soc. 1994, 116, 9753.
(10) The corresponding pinacol boronic acids were ineffective
reagents.
B
Org. Lett., Vol. XX, No. XX, XXXX

handles for further synthetic manipulation (Table 2, entries
12À14). The O-alkenyl benzophenone oximes prepared as
described in Table 2 were subsequently tested for [1,3]-
rearrangement reactivity to access a variety of R-imino
aldehydes.
Table 4. [1,3]-Rearrangement and Olefination
Table 2. Scope of O-Alkenyl Benzophenone Oxime Preparation
entry
R
4a (yield, %)
5b (yield, %)
1
Me
4a (56)
4b (72)
4c (62)
4d (63)
4e (72)
4f (64)
4g (66)
4h (39)c
4i (22)d
4k (56)
4l (63)
5a (52)
5b (69)
5c (66)
5d (54)
5e (70)
5f (64)
5g (63)
5h (26)c
2
n-Bu
n-Hex
i-Pr
Cy
3
4
entry
R
3a(yield, %) entry
R
3a(yield, %)
5
6
t-Bu
Bn
1
2
3
4
5
6
7
Me
3a (90)
3b (89)
3c (96)
3d (83)
3e (84)
3f (61)
3g (78)
8
ÀCH(Ar)(Et)
Àcyclopropyl
ÀCH2OTBS
À(CH2)2OBn
À(CH2)4Cl
3h (69)
3i (56)
3j (71)
3k (82)
3l (73)
3m (64)
3n (96)
7
n-Bu
n-Hex
i-Pr
Cy
9
8
ÀCH(Ar)Et
cyclopropyl
À(CH2)2OBn
À(CH2)4Cl
10
11
12
13
14
9
10
11
12
13
5k (51)
5l (52)
t-Bu
Bn
À(CH2)3CO2Me
À(CH2)3CN
À(CH2)3CO2Me
À(CH2)3CN
4m (56)
4n (58)
5m (52)
5n (55)
a Percent isolated yields. Ar = p-t-Bu(C6H4).
a Percent yield determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. b Percent isolated yield.
c dr = 1:1. d No evidence of ring-opening was observed. Ar = p-t-Bu(C6H4).
When oxime ether 3b was heated to 75 °C in dioxane-d8,
the corresponding R-imino aldehyde 4b was observed by
1H NMR spectroscopy (Table 3, entry 1). This product
could be isolated as a crude oil but hydrolyzed in the
presence of silica gel. Dioxane was initially selected as
an appropriate medium for the rearrangement since it
had previously been identified as the most effective
solvent for the [1,3]-rearrangement and condensation of
acetophenone-based O-alkenyl oximes to give the corre-
sponding pyrroles.5 As described in Table 3, a solvent
screen showed that the preparation of 4b was less efficient
in aromatic and halogenated solvents, as well as THF
(entries 2À4). Reaction time and temperature also played a
dependent role on the efficiency of the transformation:
faster rearrangements were achieved at higher tempera-
tures and gave higher yields (Table 3, entries 5 and 6).
The optimal conditions described in Table 3, entry 6, were
ultimately chosen to screen the scope of the O-alkenyl
benzophenone oxime [1,3]-rearrangement.
A variety of oxime ethers 3 were evaluated for both
thermal [1,3]-rearrangements to give R-imino aldehydes 4
as well as a single flask, thermal rearrangement, and HWE
olefination sequence to form isolable γ-imino-R,β-unsatu-
rated esters 5. These transformations were shown to be
general for the majority of the O-alkenyl oximes described
in Table 2, and the isolated yields of 5 correlate appro-
priately with the corresponding observed yields of 4,
determined by 1H NMR spectroscopy. As shown in Table 4,
trans-alkenyl oxime ethers with linear and branched alkyl
substituents were well-tolerated for these transformations
(entries 1À7). Chloro-, ester-, and cyano-functionalized
substrates also provided the corresponding R-imino alde-
hydes and γ-imino-R,β-unsaturated esters in good yields
(Table 4, entries 11À13). Surprisingly, only benzyl ether 3k
was efficiently converted to 4k and 5k, while silyl ether 3j
decomposed under the [1,3]-rearrangement conditions.
Alkenyl oxime ether 3h provided 1:1 diastereomeric mix-
tures of 4h and 5h, which implied that the stereochemistry
of the rearrangement cannot be controlled by the alkenyl
boronic acid substituent. Vinylcyclopropane-substituted
oxime ether 3i underwent a rearrangement to 4i in low
yield; however, the lack of any evidence of ring-opening
suggests that the transformation is not proceeding by a
radical pathway.13 With a variety of γ-imino-R,β-unsatu-
rated esters in hand, simple imine hydrolysis conditions
were also determined to remove the imine protecting group
and release the free amine for further manipulation
(Scheme 2).
Table 3. Optimization of [1,3]-Rearrangement
entry
solvent
time (h)
temp (°C)
yieldb (%)
1
2
3
4
5
6
dioxane-d8
toluene-d8
DCE-d4
3
75
75
67
38
62
25
19
72
3
3
75
THF-d8
3
75
dioxane-d8
dioxane-d8
8
50
0.5
100
a 0.1 M solutions. b Percent yield determined by 1H NMR spectros-
copy using 1,3,5-trimethoxybenzene as an internal standard.
While the lack of any evidence of ring-opening for the
rearrangement of 3i suggests that the [1,3]-rearrangements
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Imine Hydrolysis and Protection
Scheme 3. Crossover Experiment
of O-alkenyl oximes do not proceed through a single-
electron pathway, we were still interested in determining
if the transformation was proceeding through a dissocia-
tive mechanism.14À16 As shown in Scheme 3, a crossover
experiment between oxime ethers 3a and 7 provided
four distinct products. This result suggests that the [1,3]-
rearrangement can occur through solvent separated inter-
mediates and may be proceeding through an ion-pair
pathway.15,17 To compare the enthalpy of activation for
the [1,3]-rearrangement to reported NÀO bond dissocia-
tion energies, first order rate constants for the rearrange-
ment were determined at five points between 40 and 80 °C
and used to form an Eyring plot. The following activation
parameters were determined from these data: ΔHq =
25.4 kcal/mol and ΔSq = À0.8 eu.18 While the experi-
mental activation enthalpy value is lower than the reported
NÀO bond dissociation energy value for O-phenyl benzo-
phenone oxime (34.9 kcal/mol), it suggests that the oxime
ether NÀO bond is significantly weakened during the
rate-determining step of the [1,3]-rearrangement and
supports the observation of crossover products through
a dissociative mechanism.19
In summary, we have shown that R-imino aldehydes can
be prepared directly from alkenylboronic acids through a
copper-mediated CÀO bond coupling with benzophenone
oxime and a subsequent [1,3]-rearrangement. Inanalogyto
other protected R-amino aldehydes, these products under-
go HWE reactions to provide γ-imino-R,β-unsaturated
esters that can be hydrolyzed to release the free amine.
The [1,3]-rearrangement of O-alkenyl benzophenone ox-
imes described above provides an alternative route to an
important synthetic intermediate that avoids the use of
amino acid starting materials or aldehyde precursors and
provides access to R-imino aldehydes directly from alkynes
via simple hydroboration.
(14) For mechanistic discussions and examples of [1,3]-rearrange-
ments of allyl vinyl ethers, see: (a) Nasveschuk, C. G.; Rovis, T. Org.
Biomol. Chem. 2008, 6, 240. (b) Grieco, P. A.; Clark, J. D.; Jagoe, C. T.
J. Am. Chem. Soc. 1991, 113, 5488. (c) Gansauer, A.; Fielenbach, D.;
Stock, C.; Geich-Gimbel, D. Adv. Synth. Catal. 2003, 345, 1017. (d)
Nasveschuk, C. G.; Rovis, T. Org. Lett. 2005, 7, 2173.
(15) For examples of [1,3]-rearrangements of isoxazolines that likely
proceed through radical mechanisms, see: (a) Ishikawa, T.; Kudoh, T.;
Yoshida, J.; Yasuhara, A.; Manabe, S.; Saito, S. Org. Lett. 2002, 4, 1907.
(b) Gayon, E.; Debleds, O.; Nicouleau, M.; Lamaty, F.; van der Lee, A.;
Vrancken, E.; Campagne, J. M. J. Org. Chem. 2010, 75, 6050. (c)
Baldwin, J. E.; Pudussery, R. G.; Qureshi, A. K.; Sklarz, B. J. Am.
Chem. Soc. 1968, 90, 5325.
Acknowledgment. We thank Prof. T. G. Driver (UIC)
for insightful discussions and chemicals and Mr. Furong
Sun (UIUC) for mass spectrometry data. We also thank
the ACS PRF (DNI 50491), the NSF (NSF-CHE
1212895), and UIC for funding.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This in-
formation is available free of charge via the Internet at
http://pubs.acs.org.
(16) For a discussion of [1,3]-rearrangements of O-vinyl oxime
ethers, see: Shagun, V. A.; Sinegovskaya, L. M.; Toryashinova, D.-S.
D.; Tarasova, O. A.; Trofimov, B. A. Russ. Bull. Chem. 2001, 50, 732.
(17) Carpenter, B. K. Determination of Organic Reaction Mechanism;
John Wiley & Sons: New York, 1984.
(19) Blake, J. A.; Pratt, D. A.; Lin, S.; Walton, J. C.; Mulder, P.;
Ingold, K. U. J. Org. Chem. 2004, 69, 3112.
(18) See the Supporting Information for a discussion of the Eyring
study.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX