Catalytic synthesis of nonracemic azaproline derivatives by cyclization of β-alkynyl hydrazines under kinetic resolution conditions

Article abstract of DOI:10.1002/anie.201101090

No metals required: Starting from readily accessible γ-silyl allenyl esters, β-alkynyl hydrazines were prepared in one step and subsequently cyclized in the presence of ammonium and phosphonium catalysts leading to dehydroazaproline products (see scheme;

Full text of DOI:10.1002/anie.201101090

Communications
DOI: 10.1002/anie.201101090
Alkyne Activation
Catalytic Synthesis of Nonracemic Azaproline Derivatives by
Cyclization of b-Alkynyl Hydrazines under Kinetic Resolution
Conditions**
Pradip Maity and Salvatore D. Lepore*
Heteroatom addition reactions to unactivated alkynes are
thought to be best mediated by transition-metal catalysts such
as palladium[1] and gold.[2] Recent studies by Hammond and
co-workers[3] and others[4] demonstrate that cyclizations of
alkynes with nitrogen- and oxygen-containing nucleophiles
are possible using stoichiometric amounts of tetra-n-butyl-
ammonium fluoride. However, these examples appear to be
limited to aryl or a,a-difluoro alkynes. As described herein,
we have discovered by serendipity a nonmetal catalyzed
addition of amine to unactivated alkynes to yield azaproline
derivatives (Scheme 1). Although the nature of this catalysis
reaction is not clear, these reactions proceed in excellent
yields and lead to enantioenriched azaprolines under kinetic
resolution conditions using ammonium phase-transfer cata-
lysts.
titanium BINOL-ate.[10] The pyrazolidine ring of azaprolines
has also been prepared by palladium-catalyzed cyclizations of
optically active allenylic hydrazines[11] or hydrazine adducts
produced from racemic allenyl phosphine oxides.[12] However,
herein we report related cyclization reactions catalyzed by
nonmetal cations, which have allowed for an exciting class of
chiral ammonium phase-transfer catalysts to be brought to
bear to produce nonracemic azaproline derivatives
(Scheme 1).
Based on our previous experience with g-silyl allenyl
esters,[13] we hypothesized that base-catalyzed addition of
dinitrogen-containing electrophiles such as azidodicarboxy-
lates should lead to b-alkynyl hydrazine intermediates.
Indeed, with substrates 1 and 2 (EWG = CO2tBu and
CO2Et) DBU catalyzed this transformation but the reactions
were sluggish especially with larger a-substituents
(Table 1).
By applying a procedure similar to one we had
previously reported,[14] g-silyl allenyl and propargyl thio-
esters (EWG = COStBu) were prepared and, as expected,
these substrates underwent rapid addition to azidodicar-
boxylates with DBU even at À208C. Less basic amines
failed to give hydrazine products even with these thio-
Scheme 1. Catalytic generation of azaprolines by cyclization of b-alkynyl
hydrazine compounds. EWG=electron-withdrawing group.
Table 1: Additions of allenyl esters to azidodicarboxylates catalyzed by
DBU.
We decided to further investigate this cyclization reaction
partly out of mechanistic curiosity but also mindful that
azaprolines have taken on an increasingly important role in
bioorganic[5] and medicinal chemistry.[6] Indeed, there has
been a great deal of interest in the synthesis of azaproline
derivatives over the last decade. The earliest approach
pioneered by Carreira and co-workers involved diastereose-
lective [3+2] additions of diazoalkanes with a,b-unsaturated
chiral esters.[7] More recently this method has been expanded
to include other dipolar diazo reactions[8] including those
catalyzed by chiral magnesium bisoxazole[9] as well as
Entry EWG
R1
SiR3
R2
T [8C] t [h] Yield [%][a]
1
2
3
4
5
6
7
8
CO2tBu
Ph
H
H
TES
TES
TES
TES
TMS iPr
TIPS iPr
TES
TES
TES
TES
iPr
iPr
Bn
iPr
RT
0
0
À20
À20
À20
12
4
4
1
1
1
1
1
1
1
1
83
87
67
69
67
75
78
71
76
79
68
CO2Et
CO2Et
COSBu
COStBu Ph
COStBu Ph
COStBu Ph
COStBu vinyl
COStBu 2-naph
COStBu o-tol
Ph
[*] P. Maity, Prof. S. D. Lepore
tBu À20
Department of Chemistry, Florida Atlantic University
Boca Raton, FL 33431 (USA)
E-mail: slepore@fau.edu
iPr
iPr
iPr
iPr
À20
À20
À20
À20
9
10
11
Homepage: http://www.science.fau.edu/chemistry/faculty/Lepore
COStBu p-ClC6H4 TES
[**] The work was supported by the National Institutes of Mental Health
(087932-01) and the NSF (0311369).
[a] Yield of isolated product. With thioester substrates <5% of g-
addition hydrazine products (allenes) were also observed. Bn=benzyl,
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, naph=naphthyl, TES=tri-
ethylsilyl, TIPS=triisopropylsilyl, tol=tolyl, TMS=trimethylsilyl.
Supporting information, including spectroscopic data on all
products, for this article is available on the WWW under http://dx.
doi.org/10.1002/anie.201101090.
8338
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Angew. Chem. Int. Ed. 2011, 50, 8338 –8341

Table 3: Role of cation and anion in catalyzed cyclization of 4.
esters except with DMF as the reaction solvent. The DMF
solvent gave no enantioselectivity when chiral amine catalysts
such as quinine were used to catalyze the addition reaction to
give 4.
For improved characterization, we thought it useful to
remove the silyl group from product 4. However, we were
surprised to discover that the desilylation of 4 using tetra-n-
butylammonium fluoride (TBAF) led to dehydroazaproline 5
in nearly quantitative yields. Our subsequent studies of this
system revealed that the ammonium salt acts catalytically to
form the heterocycle and that the reaction appears to tolerate
a variety of substituents at the quaternary carbon center
(Table 2). We note that the TBAF used was a commercially
Entry
Cat.
Additive (equiv)
Yield [%][a]
1
2
3
4
5
6
7
TBAF
TBAB
TBAB
TBPB
TBPB
TBAB
TBPB
–
–
99
NR
97
NR
98
95
94
CsF (0.5)
–
CsF (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
NR=no reaction.
Table 2: Cyclization of b-alkynyl hydrazines catalyzed by TBAF.
need not be fluoride as added carbonate leads to the same
result with TBAB (Table 3, entry 6).
Interestingly, tetra-n-butylphosphonium bromide (TBPB)
also effectively catalyzed the cyclization[15] with either fluo-
ride or carbonate additives. Clearly, neither ammonium nor
fluoride is strictly required to catalyze this cyclization
reaction.
The discovery that the present cyclization reaction is
mediated by catalytic nonmetal cations suggested that kinetic
resolution might be possible. Our initial experiments with a-
benzyl ester and chiral ammonium bromides 7 and 8 (Table 4,
entries 1 and 2) gave no reaction. However, less steric bulk at
the quaternary carbon center led to successful reactions
(Table 4, entries 4–7) that proceed fairly rapidly to approx-
imately 50% conversion with catalysts 7 and 8. Importantly,
this reaction led to products (and recovered starting materi-
als) of high enantioselectivity. Catalysts containing the
bromide counter ion required added CsF to afford product.
This cyclization reaction is particularly sensitive to steric
Entry
EWG
R1
R2
SiR3
Yield [%][a]
1
CO2tBu
COStBu
COStBu
COStBu
COStBu
CO2Et
COStBu
COStBu
COStBu
COStBu
CO2Et
Ph
Ph
Ph
Ph
Ph
H
vinyl
p-ClC6H4
o-tol
2-naph
H
iPr
iPr
iPr
iPr
tBu
iPr
iPr
iPr
iPr
iPr
Bn
iPr
TES
TES
TMS
TIPS
TES
TES
TES
TES
TES
TES
TES
TES
99
97
98
99
94
99
99
99
99
99
99
97
2[b]
3
4
5
6
7
8
9
10
11
12[c]
CONR2
vinyl
[a] Yield of isolated product. [b] Starting with nonracemic 4 led to
product with the same ee value. [c] Amide derivative of pyrrolidine.
THF=tetrahydrofuran.
Table 4: Nonracemic azaproline products by kinetic resolution.
available solution in THF containing up to 5% dissolved
water, which is likely the stoichiometric agent responsible for
removal of the silyl group. Although the present TBAF-
catalyzed cyclization step is unprecedented, another study
details the cyclization of aryl alkynes with nitrogen- and
oxygen-containing nucleophiles mediated by stoichiometric
amounts TBAF.[4] In addition, Hammond and co-workers
describe a cyclization with a nitrogen-containing nucleophile
with an alkyne flanked with an a,a-difluoro methylene that
requires two equivalents of TBAF.[3]
To better understand the role of the nonmetal catalyst in
the present reaction, several factors were examined. To
separate issues of desilylation versus cyclization, we prepared
silyl-free substrate 6 using stoichiometric amounts of TBAF in
isopropanol (alcohol solvents do not lead to cyclization
products). Now, using TBAF as the catalyst (0.1 equiv), the
cyclization reaction of 6 gave excellent yields in THF, CH2Cl2,
and toluene. The use of tetra-n-butylammonium bromide
(TBAB) as a catalyst gave no cyclization product except with
the addition of CsF (Table 3, entry 3). However, the anion
Entry EWG
R1
R2 Cat. Additive t [h] Yield [%][a] ee [%][b]
1
2
4
5
CO2Et
CO2Et
CO2Et
CO2Et
Ph
Ph
H
iPr 7-Br CsF
iPr 8-Br CsF
Bn 7-Br CsF
12 NR
12 NR
–
–
48
48
12
12
1
47
48
54
51
93[c]
93[c]
76
H
Bn 7-F
–
6
COStBu vinyl iPr 8-Br CsF
7
COStBu vinyl iPr 8-F
COStBu vinyl iPr TBAF
CONR2 vinyl iPr 8-F
–
–
–
81
8
quant.
99[d]
4
9[e]
8
73[f]
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase. [c] Based on analysis of remaining starting material by
using HPLC on a chiral stationary phase. [d] Recovered starting material
from previous reaction (entry 7) was utilized. [e] Amide of pyrrolidine.
[f] Recovered 25% starting material.
Angew. Chem. Int. Ed. 2011, 50, 8338 –8341
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8339

Communications
crowding. Thus with allyl substitution at the a position,
have been prepared using readily available chiral ammonium
salts as catalysts. Further mechanistic studies and exploration
of the reactivity of the dehydroazaproline system are
currently underway.
catalyst 7 proved ineffective whereas the much smaller 8 led
to product with good resolution (Table 4, entries 6 and 7). As
expected, recovered starting material from a kinetic resolu-
tion reaction (Table 4, entry 7) led to cyclization product 5 in
high enantiomeric excess using catalytic amounts of TBAF
(Table 4, entry 8).
Experimental Section
It appears that a modestly basic counteranion (FÀ or
CO32À) is required for this cyclization reaction—presumably
to deprotonate the attacking carbamate nitrogen center.
Hiroya, Sakamoto, and co-workers have proposed an ammo-
nium cation activation of alkynes in cycloaddition reactions
involving aryl alkynes.[4a] While additional theoretical and
physical investigations are needed to substantiate these
claims, we remain intrigued by the possibility that the
carbamate nitrogen-centered nucleophile in our case attacks
the alkyne group similarly activated by an ammonium or
phosphonium catalyst. In this manner, the catalyzing ability of
a chiral organic cation is expected to be influenced by the
configuration of the quaternary center immediately adjacent
to the alkyne: thus, perhaps explaining our successful kinetic
resolution in this cyclization reaction.
The main thrust of this project was to develop a kinetic
resolution technique to take advantage of the unprecedented
nonmetal-catalyzed cyclic heteroatom addition mentioned
above. Nevertheless we briefly explored asymmetric phase-
transfer-catalyzed additions of azidodicarboxylates to our g-
silyl allenyl ester system by using a recent precedent by
Maruoka and co-workers involving carbon electrophiles.[16]
While aqueous/organic biphasic systems resulted in no
reaction with allenyl oxyesters, we observed that
CsOH·H2O in toluene led to their successful hydrazination.
However, this solid/liquid phase reaction led to entirely
racemic product when a variety of commercially available
phase-transfer catalysts (PTC) we employed.[17] We returned
to the organic/aqueous systems with thioester substrates and
observed addition products in good yields and moderate
enantioselectivities [Eq. (1)]. For this study we employed
several commercially available PTCs including cinchona-
based catalysts and Maruoka catalyst 7. These results suggest
that a suitable catalyst can be engineered for higher selectiv-
ities.
Neutral base-catalyzed a-amination: Allene/alkyne mixture
(1 mmol) was added to a round-bottom flask which was then charged
with solvent (5 mL). The mixture was cooled to the required
temperature before base (20 mol%) was added. After 5 min of
stirring, azidodicarboxylate (1.2 equiv) was slowly added to the
mixture and the reaction was stirred. Once the reaction was complete
(as evident by TLC), the mixture was quenched with aqueous HCl
(1m). The organic layer was removed and the aqueous layer was
extracted twice with diethyl ether. All organic layers were combined,
concentrated in vacuo, and purified by flash column chromatography
on silica gel.
TBAF-catalyzed cyclization: The substrate (0.5 mmol) was
dissolved in THF (2 mL) before TBAF (1m THF, 20 mol%) was
added. The reaction was stirred for 30 min, quenched with aqueous
HCl (1m) and extracted with diethyl ether. The organic layer was
removed and the aqueous layer was extracted twice with diethyl
ether. All organic layers were combined, concentrated in vacuo, and
purified by flash column chromatography on silica gel to give nearly
quantitative yield of product.
General procedure for kinetic resolution with ammonium
fluoride catalysts: Substrate (0.5 mmol) was added to a round-
bottom flask which was then charged with toluene (5 mL). Catalyst
(10 mol%) was then added and the mixture was stirred for the
required time. The reaction was quenched with aqueous HCl (1m) and
extracted with diethyl ether. All organic layers were combined,
concentrated in vacuo, and purified by flash column chromatography
on silica gel. The enantiomeric excesses of the separated products and
starting materials were determined by HPLC on a chiral stationary
phase.
Received: February 13, 2011
Revised: June 29, 2001
Published online: July 15, 2011
Keywords: alkyne activation · b-alkynyl hydrazines ·
.
dehydroazaprolines · kinetic resolution · organocatalysis
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Angew. Chem. Int. Ed. 2011, 50, 8338 –8341

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