Effect of Substituents and Stability of Transient Aluminum-Aminals in the Presence of Nucleophiles

Article abstract of DOI:10.1055/s-0034-1379635

Disubstituted hydroxylamines are synthesized and used to form aluminum-amide complexes. These reagents mask carbonyl groups in situ via nucleophilic addition. The stability and utility of the aluminum-aminals are presented in the context of selectively controlling nucleophilic addition on substrates with multiple carbonyl groups.

Full text of DOI:10.1055/s-0034-1379635

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 175–180
feature
175
F. J. Barrios et al.
Feature
Synthesis
Effect of Substituents and Stability of Transient Aluminum–
Aminals in the Presence of Nucleophiles
Francis J. Barriosa
R2
R4
aluminum–amide reagent
R2
transiently
masked
carbonyl
group
Brannon C. Springerb
Robert A. Hazlittb,c
David A. Colby*b,c
O
Al
O
R2
Al
R2
OR4
R3
O
N
R3
N
H
H
R1
R1
a Department of Chemistry and Physics, Bellarmine University,
2001 Newburg Rd., Louisville, KY 40205, USA
b Department of Chemistry, Purdue University, 560 Oval Drive,
West Lafayette, IN 47907, USA
c Department of BioMolecular Sciences, University of Mississip-
pi, 317 Faser Hall, P.O. Box 1848, University, MS 38677, USA
dacolby@olemiss.edu
O
stable aminal
O
R1 = Me, OMe
R2 = Me, i-Bu
R
R
3 = Me, Et, allyl, Bn
4 = Me, Bn, 4-methoxybenzyl, naphthylmethyl
Received: 15.10.2014
Accepted after revision: 17.11.2014
Published online: 05.12.2014
Me
O
M
O
R2
M
OMe
O
N
R1
N
DOI: 10.1055/s-0034-1379635; Art ID: ss-2014-m0630-fa
Me
R1
R2
Me
Abstract Disubstituted hydroxylamines are synthesized and used to
form aluminum–amide complexes. These reagents mask carbonyl
groups in situ via nucleophilic addition. The stability and utility of the
aluminum–aminals are presented in the context of selectively con-
trolling nucleophilic addition on substrates with multiple carbonyl
groups.
stable aminal
R3
Al
R3
OMe
Me
R3
Me
R3
N
O
Al
O
O
N
R1
R2
Me
R1
stable aminal
Scheme 1 Strategies for the formation of stable aminals
R2
Key words aluminum, amides, amines, nucleophilic addition, carbon-
yl complexes
Carbonyl groups are prominent functional groups on
many organic compounds and naturally occurring mole-
cules. The careful manipulation of these groups and control
of their reactivity as electrophiles is critical in the synthesis
of complex targets.1–3 The primary methods to address
these issues are the use of carbonyl protecting groups or
the implementation of oxidation/reduction strategies. An
alternative tactic is the incorporation of a Weinreb amide,
an aldehyde or a ketone precursor into the synthesis.4,5 The
process of transforming a Weinreb amide into a carbonyl
group requires a nucleophilic addition that results in the
formation of a transient, but stable, aminal (Scheme 1).6,7
This aminal is resistant to subsequent nucleophilic attack,
but collapses to a carbonyl in the presence of aqueous acid.
In 2010, we demonstrated the effectiveness of trapping
reactive carbonyl groups as aminals using an aluminum–
amide complex rather than forming them from Weinreb
amides (Scheme 1).8 This aluminum complex is prepared
from diisobutylaluminum hydride (DIBAL-H) and N,O-di-
methylhydroxylamine. It is an alternative to prior methods
of using highly basic lithium–amides.9–12 The intermediate
aluminum–aminal is resistant to different types of reactive
nucleophiles such as Grignard reagents and organolithiums.
Using this in situ masking method, selective additions to es-
ters were accomplished in the presence of aldehydes and
ketones (Table 1). In a similar fashion, selective additions to
ketones in the presence of aldehydes were executed. Specif-
ically, the more reactive carbonyl group was trapped after
treatment with a mixture of diisobutylaluminum hydride
and N,O-dimethylhydroxylamine. One equivalent of isopro-
pylmagnesium chloride was used as a base to remove the
last acidic proton and stabilize the aminal. Substrates 1–3,
each containing two distinct carbonyl groups, readily par-
ticipated and the products 4–6 were isolated in good yields
with either an organolithium or Grignard reagent adding
selectively to the less reactive carbonyl group.
This methodology enables the aluminum–amide to add
to the more reactive carbonyl group and eliminate its elec-
trophilic nature by creating a stable aminal following addi-
tion of a base, usually isopropylmagnesium chloride. A
drawback of this approach is the use of a base to remove the
last acidic proton and stabilize the aminal intermediate. By
redesigning the generation of the aminal and adding the
base earlier in the sequence, we speculated that the scope
of compatible reactions would be enhanced. Specifically,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 175–180

176
F. J. Barrios et al.
Feature
Synthesis
we aimed to create a discrete aluminum reagent that would
form the aminal in one step.13 In order to achieve this objec-
tive, adding n-butyllithium or isopropylmagnesium chlo-
ride to N,O-dimethylhydroxylamine hydrochloride succeed-
ed in consuming the acidic proton of the hydrochloride, and
then subsequent treatment with trimethylaluminum
formed the requisite aluminum–amide complex. Substrates
1–3, each with two distinct carbonyl groups, participated in
this more efficient method and provided access to products
4–11 upon addition of organolithiums, Grignard reagents,
reducing reagents, Wittig reagents, and enolate anions (Ta-
ble 2). High levels of chemoselectivity were observed, good
yields of products were isolated, and the scope of the reac-
tion was enhanced as more nucleophiles participated in the
process.
Biographical Sketches
Francis J. Barrios completed
B.S. in chemistry at the Univer-
sity of Puerto Rico at Mayaguez
and earned a PhD in organic
chemistry from Purdue Univer-
sity (USA) in 2013. He joined
the faculty at Westminster Col-
lege in the Department of
Chemistry as a visiting assistant
professor and then was promot-
ed to assistant professor. He is
currently an assistant professor
in the Department of Chemistry
and Physics at Bellarmine Uni-
versity in Louisville, Kentucky
(USA).
Brannon C. Springer received
a B.S. in biochemistry at Purdue
University (USA) in 2014. She
was a technology intern at SAB-
IC Innovative Plastics and is cur-
rently a Quality Control chemist
at KIK Custom Products.
Robert A. Hazlitt earned a
B.S. in chemistry at Baylor Uni-
versity (USA) in 2010. He was a
chemical technician at the Dow
Chemical Company. He is cur-
rently a Ph.D. candidate at Pur-
due
University
in
the
Department of Chemistry in the
Division of Organic Chemistry.
David A. Colby received
a
Research Institute with Prof.
Dale Boger. He joined the facul-
ty at Purdue University in 2008
as an assistant professor in the
ment in the Department of
Chemistry. In 2014, he moved
to the University of Mississippi
as an Associate Professor of Me-
dicinal Chemistry in the Depart-
ment of BioMolecular Sciences.
Pharm.D. at the University of
Iowa (USA) and completed his
Ph.D. in organic chemistry at
the University of California at Ir-
vine. He conducted postdoctor-
al research at the Scripps
Department
of
Medicinal
Chemistry and Molecular Phar-
macology with a joint appoint-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 175–180

177
F. J. Barrios et al.
Feature
Synthesis
Table 1 Stability of Aluminum–Aminals to Nucleophilic Additions
i. DIBAL-H, HN(OMe)Me•HCl
ii. i-PrMgCl, RM, then H2O
substrate
product
1–3
4–6
Entry
Substrate
R–M
Product
O
Yielda
87%
O
H
H
1
n-BuLib
OMe
O
OH
1
1
4
O
H
2
MeMgBr
70%
OH
5
5
5
O
H
3
4
5
6
MeLi
63%
86%
83%
76%
O
2
2
MeMgBr
MeLib
O
O
OMe
O
OH
3
3
6
6
MeMgBr
a Yield of isolated product.
b An organolithium was used instead of i-PrMgCl.
Next, the stability of the aluminum–amide complex was
investigated across three weeks (Table 3).14 A 0.5 M solution
of the aluminum–amide reagent in tetrahydrofuran was
prepared using N,O-dimethylhydroxylamine hydrochloride,
n-butyllithium, and trimethylaluminum and stored at 0 °C.
This reagent was used to transform methyl 4-formylbenzo-
ate (1) into the alcohol 4 following treatment with n-butyl-
lithium. The reagent performed superbly at the time points:
one hour, one day, one week, two weeks, and three weeks
when compared to the baseline reaction yield of 91% fol-
lowing immediate use. A slight enhancement in yields was
observed and this result may be attributed to the additional
time that the reagent has to form the aluminum–aminal
complex.
amine were replaced by other large alkyl groups (Scheme
2). We have already demonstrated that the aluminum spe-
cies can be derived from trimethylaluminum or diisobutyl-
aluminum hydride and that the respective methyl or isobu-
tyl group is compatible with the process. The next site to in-
vestigate was the contribution made by substituents on the
nitrogen and oxygen of the hypothesized aluminum–
aminal intermediate.
Me
OR1
R2
R1
Me
Al
Al
N
Me
O
O
Me
O
N
R2
H
Ar
R1 = alkyl
2 = alkyl
H
Ar
R
Scheme 2 Design of aluminum–amide reagents to evaluate the ef-
fects of substituents on the nitrogen and oxygen atoms
Following the collection of these promising data, the
aminal was redesigned in an effort to understand its stabili-
ty when the methyl groups on the N,O-dimethylhydroxyl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 175–180

178
F. J. Barrios et al.
Feature
Synthesis
Table 3 Effect of Time on the Reagent Prior to Formation of the Aminal
Table 2 Stability of Aluminum–Aminals Formed by a Reagent
i. HN(OMe)Me•HCl, n-BuLi, Me3Al
i. Me2AlN(OMe)Me·LiCl
solution in THF (0.5 M)
substrate
product
1
4
1–3
4–11
ii. RM, then H2O
ii. n-BuLi, then H2O
Entry
1
Substrate R–M
Product
Yielda
91%
Entry
Time of storage of the reagent at 0 °C (step i)a
Yieldb
1
1
n-BuLi
4
1
2
3
4
5
6
immediate use
one hour
91%
99%
99%
97%
98%
99%
O
one day
H
2
allylMgBrb
83%
one week
two weeks
three weeks
OH
7
a A 0.5 M solution of the aluminum–amide reagent in THF was prepared us-
ing HN(OMe)Me·HCl, n-BuLi, and Me3Al, which was then stored at 0 °C.
b Yield of isolated product.
O
H
3
4
1
2
DIBAL-Hb
MeLi
89%
86%
OH
8
5
amine 17 was synthesized from O-benzylamine hydrochlo-
ride 16 with benzyl bromide in the presence of potassium
carbonate.16
O
H
5
6
2
2
EtMgBrb
85%
86%
O
1. K2CO3, R1Br
DMSO
1. Boc2O
H2O
N
OH
H2N OR1
OH
2. NH2NH2, EtOH
reflux
2. NaH, R2I
THF
9
13
O
O
12
Boc
O
R2
O
TFA
H
N
R2
R1
N
R1
Ph3P=CH2
H
CH2Cl2
15a–d
14
10
O
NH3Cl
H
N
BnBr, K2CO3
DMF
O
OLi
H
O
7
8
2
3
70%
70%
16
17
OEt
CO2Et
Scheme 3 Two synthetic routes toward substituted hydroxylamines
HO
11
6
MeMgBr
The utility of the new aluminum–amide precursors was
investigated by treating the amines with trimethylalumi-
num and using them for the in situ masking of the carbonyl
groups on substrates 1 and 2 (Table 4). The selective addi-
tion of n-butyllithium and ethylmagnesium bromide to the
less reactive carbonyl group was examined and compared
to the isolated yields when N,O-dimethylhydroxylamine
was used as the precursor. Typically, the major product was
isolated in modest to good yields, and these yields were
lower than those observed with N,O-dimethylhydroxyl-
amine. Specifically, the use of amine 15a that possesses an
ethyl and a benzyl group provided a moderate yield of
product 4. Exchanging the ethyl group for an allyl group
(i.e., amine 15b) had a minimal effect on the yield com-
pared to 15a. Similarly, the amine 15c with a p-methoxy-
benzyl substituent provided a yield similar to the benzyl
a Yield of isolated product.
b i-PrMgCl was used instead of n-BuLi.
Two synthetic strategies for the N,O-dialkylhydroxyl-
amines were undertaken according to the literature prece-
dents for these new stability studies (Scheme 3).15,16 A com-
bination of N-hydroxyphthalimide (12) and different ben-
zyl halides, on treatment with hydrazine, generated the
corresponding O-benzylhydroxylamines 13. Amines 13
were protected and the intermediate carbamates treated
with sodium hydride and an alkyl iodide to give the carba-
mates 14. Acidolysis of carbamates 14 with trifluoroacetic
acid provided the corresponding N,O-dialkylhydroxyl-
amines 15a–d. Alternatively, the N,O-dibenzylhydroxyl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 175–180

179
F. J. Barrios et al.
Feature
Synthesis
Table 4 Effects of the Substitution Pattern of Hydroxylamines on the Stability of the Aminal
i. amine (15a–d, 17), Me3Al
substrate
product
1, 2
4, 9
ii. RM, then H2O
Entry
1
Substrate
Amine
HN(OMe)Me·LiClb
R–M
Product
Yielda
1
n-BuLi
4
91%
H
N
O
2
3
1
1
n-BuLi
4
4
58%
15a
15b
H
N
O
n-BuLi
n-BuLi
67%
66%
H
N
O
4
1
4
MeO
15c
5
6
2
2
HN(OMe)Me·LiClb
EtMgBr
EtMgBr
9
9
85%
72%
H
N
O
15d
H
N
O
7
2
EtMgBr
9
51%
17
a Yield of isolated product.
b Formed from n-BuLi and HN(OMe)Me·HCl.
amine 15b. The highest yield was obtained using the naph-
thyl-substituted amine 15d, however, the lowest yield was
obtained when using the dibenzyl amine 17. Overall, the
yields of products 4 and 9 were in the range of 51–72% and
these are somewhat lower than those obtained using N,O-
dimethylhydroxylamine (85–91%). The conclusion is that
exchanging the methyl substituents of N,O-dimethylhy-
droxylamine with other alkyl groups is well tolerated with
only a modest effect on the yields.
In conclusion, we have demonstrated that aluminum
complexes derived from N,O-dialkylhydroxylamines can
serve as reagents to trap reactive carbonyl groups as ami-
nals from reactive nucleophiles, and that there is substan-
tial flexibility in the implementation of this method. The
broad scope of this process has been established by synthe-
sizing and reacting N,O-dialkylhydroxylamines with differ-
ent carbonyl-group-containing substrates. The effect of us-
ing different substituents on the nitrogen atom was modest
despite exchanging methyl groups with substantially larger
substituents. These data are compelling as they lay a foun-
dation to design new classes of reagents in which these sub-
stituents can potentially participate in synthetic transfor-
mations or direct addition reactions along with masking of
the carbonyl group from nucleophiles.
Compounds 4–68 and 7–1113 have been previously described. Synthe-
ses of amines 15a,17 15b,18 15c,19 15d,20 and 1716 were conducted ac-
cording to the literature methods. Characterization data for known
compounds matched with those described in previous reports. Flash
chromatography was carried out using Silaflash p60 silica gel (230–
400 mesh 60 grade).
Formation of the Aluminum–Aminal Followed by Addition of the
Organolithium Reagent; General Procedure
To a 0 °C solution of amine 15a17 (74.9 mg, 0.49 mmol) in THF (2 mL)
was added Me3Al (250 μL, 2.0 M in hexanes). The mixture was
warmed from 0 °C to r.t. over 30 min. Next, the resultant mixture was
added to a 0 °C solution of methyl 4-formylbenzoate (1) (67 mg, 0.41
mmol) in THF (10 mL), and the mixture was stirred for 2 h at r.t. Fol-
lowing cooling to –78 °C, n-BuLi (650 μL, 2.5 M in hexanes) was add-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 175–180

180
F. J. Barrios et al.
Feature
Synthesis
ed, and the mixture was stirred for 35 min at –78 °C. The reaction was
quenched with sat. aq NH4Cl (10 mL) and extracted with EtOAc
(3 × 15 mL). The organics were dried over Na2SO4, filtered, and con-
centrated under reduced pressure. SiO2 flash chromatography
(hexanes–EtOAc, 8:2) afforded product 4 (58.8 mg, 58% yield). Charac-
terization data was identical with the reported data.8
(2) (a) Reetz, M. T.; Wenderoth, B. Tetrahedron Lett. 1982, 23, 5259.
(b) Reetz, M. T.; Wenderoth, B.; Peter, R. J. Chem. Soc., Chem.
Commun. 1983, 406. (c) Reetz, M. T.; Steinbach, R.;
Westermann, J.; Peter, R.; Wenderoth, B. Chem. Ber. 1985, 118,
1421.
(3) (a) Maruoka, K.; Imoto, H.; Yamamoto, H. Synlett 1994, 441.
(b) Maruoka, K.; Saito, S.; Yamamoto, H. Synlett 1994, 439.
(c) Maruoka, K.; Saito, S.; Concepcion, A. B.; Yamamoto, H. J. Am.
Chem. Soc. 1993, 115, 1183. (d) Maruoka, K.; Araki, Y.;
Yamamoto, H. J. Am. Chem. Soc. 1988, 110, 2650. (e) Maruoka,
K.; Araki, Y.; Yamamoto, H. Tetrahedron Lett. 1988, 29, 3101.
(4) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(5) For recent preparations of Weinreb amides, see: (a) Boufroura,
H.; Mauduit, M.; Drège, E.; Joseph, D. J. Org. Chem. 2013, 78,
2346. (b) Więckowska, A.; Fransson, R.; Odell, L. R.; Larhed, M.
J. Org. Chem. 2011, 76, 978. (c) Davis, F. A.; Theddu, N. J. Org.
Chem. 2010, 75, 3814.
Formation of the Aluminum–Aminal Followed by Addition of a
Grignard Reagent; General Procedure
To a 0 °C solution of amine 1716 (103 mg, 0.48 mmol) in Et2O–THF
(4:1, 5.5 mL) was added Me3Al (484 μL, 1.0 M in heptane). The mix-
ture was warmed from 0 °C to r.t. over 30 min. Next, the resultant
mixture was added to a 0 °C solution of 4-acetylbenzaldehyde (2) (65
mg, 0.439 mmol) in Et2O (22 mL), and the mixture was stirred for 2 h
at r.t. Following cooling to 0 °C, EtMgBr (293 μL, 3.0 M in Et2O) was
added, and the mixture was stirred for 40 min with warming from
0 °C to r.t. The reaction was quenched with sat. aq NH4Cl (20 mL) and
extracted with EtOAc (3 × 25 mL). The organics were dried over
Na2SO4, filtered, and concentrated under reduced pressure. SiO2 flash
chromatography (hexanes–EtOAc, 3:1) afforded product 9 (40 mg,
51% yield). Characterization data was identical with the reported da-
ta.13
(6) Taillier, C.; Gille, B.; Bellosta, V.; Cossy, J. J. Org Chem. 2005, 70,
2097.
(7) Taillier, C.; Bellosta, V.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6,
2145.
(8) Barrios, F. J.; Zhang, X.; Colby, D. A. Org. Lett. 2010, 12, 5588.
(9) Comins, D. L. Synlett 1992, 615.
(10) Hoffmann, R. W.; Munster, I. Tetrahedron Lett. 1995, 36, 1431.
(11) Kruger, J.; Hoffmann, R. W. J. Am. Chem. Soc. 1997, 119, 7499.
(12) Roschangar, F.; Brown, J. C.; Cooley, B. E.; Sharp, M. J.; Matsuoka,
R. T. Tetrahedron 2002, 58, 1657.
(13) Barrios, F. J.; Springer, B. C.; Colby, D. A. Org. Lett. 2013, 15,
3082.
(14) Barrios, F. J. Ph.D. Dissertation; Purdue University: USA, 2013.
(15) (a) Inomata, T.; Eguchi, H.; Funahashi, Y.; Ozawa, T.; Matsuda, H.
Langmuir 2012, 28, 1611. (b) Donkor, I. O.; Zheng, X.; Han, J.;
Lacy, C.; Miller, D. D. Bioorg. Med. Chem. Lett. 2001, 11, 1753.
(16) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem.
Soc. 2004, 126, 5192.
(17) Peri, F.; Dumy, P.; Mutter, M. Tetrahedron 1998, 54, 12269.
(18) Kolasa, T.; Miller, M. J. J. Org. Chem. 1990, 55, 1711.
(19) Wencewicz, T. A.; Yang, B.; Rudloff, J. R.; Oliver, A. G.; Miller, M.
J. J. Med. Chem. 2011, 54, 6843.
Acknowledgment
These studies were supported by Grant Number P20GM104932 from
the National Institute of General Medical Sciences (NIGMS), a compo-
nent of the National Institutes of Health (NIH), Purdue University, and
the Midwest Crossroads Alliance for Graduate Education and the Pro-
fessoriate. Its contents are solely the responsibility of the authors and
do not necessarily represent the official view of NIGMS or NIH. This
investigation was conducted in a facility constructed with support
from research facilities improvement program C06RR14503-01 from
the NIH National Center for Research Resources.
References
(20) Miyabe, H.; Asada, R.; Takemoto, Y. Org. Biomol. Chem. 2012, 10,
3519.
(1) Yahata, K.; Minami, M.; Yoshikawa, Y.; Watanabe, K.; Fujioka, H.
Chem. Pharm. Bull. 2013, 61, 1298.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 175–180