Organocatalytic α-amination-allylation-RCM strategy: enantioselective synthesis of cyclic hydrazines

Article abstract of DOI:10.1016/j.tetlet.2008.06.004

A highly enantioselective method for the synthesis of cyclic hydrazines by using organocatalytic α-amination-allylation-RCM strategy is described. Proline-catalyzed α-amination of aldehydes followed by indium-mediated one-pot allylation of the crude α-hydrazino aldehydes produces 1,2-aminoalcohols in high enantio- and diastereoselectivities. The 1,2-aminoalcohols are further converted into cyclic hydrazines by using ring-closing metathesis (RCM) reaction.

Full text of DOI:10.1016/j.tetlet.2008.06.004

Tetrahedron Letters 49 (2008) 4882–4885
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic
a-amination–allylation-RCM strategy: enantioselective
synthesis of cyclic hydrazines
*
Aram Lim, Jung Hoon Choi, Jinsung Tae
Department of Chemistry and Center for Bioactive Molecular Hybrids (CBMH), Yonsei University, Seoul 120-749, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly enantioselective method for the synthesis of cyclic hydrazines by using organocatalytic a-ami-
Received 28 April 2008
Revised 30 May 2008
Accepted 2 June 2008
Available online 5 June 2008
nation–allylation-RCM strategy is described. Proline-catalyzed
a-amination of aldehydes followed by
indium-mediated one-pot allylation of the crude -hydrazino aldehydes produces 1,2-aminoalcohols
a
in high enantio- and diastereoselectivities. The 1,2-aminoalcohols are further converted into cyclic hydr-
azines by using ring-closing metathesis (RCM) reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysts
Cyclic hydrazines
Asymmetric amination
Allylation
Ring-closing metathesis
1. Introduction
R
CHO
R
CHO
allylation
CbzN=NCbz
1
+
For the past few years, organocatalytic asymmetric synthesis1
has gained great attention, complementing bio- and metal-cataly-
sis. Several synthetic methods have been developed as practical
tools for asymmetric organic synthesis. Especially, the enantio-
N
3
Cbz
Cbz
N
H
4
CO2H
N
H
N-N bond
this work
OH
selective
a
-amination of aldehydes and ketones using proline2
cleavage
2
and its derivatives has been extensively utilized to introduce amino
groups enantioselectively. Cleavage of the N–N bond introduced by
dialkyl azidodicarboxylate (RCO2N@NCO2R) leads to synthetically
R
OH
R
RCM
a a
-amino alcohol (I)2 or -amino acid2a derivatives (Scheme
NH2
useful
1). In other ways, the
the subsequent tandem reactions such as aldol,3 Passerini,4 and
N
Cbz
I
a
-amino aldehydes were further utilized in
N
Cbz
II
Horner–Wadsworth–Emmons
reactions.5
While
allylation
reactions of proline-catalyzed aldol products6 and aminoxylation
Scheme 1. Strategy for asymmetric synthesis of cyclic hydrazines.
adducts7 are known, allylation reaction of the organocatalytic
a
-amination adducts has not been reported up to now. Although
bond by using ring-closing metathesis (RCM) reaction as the key
step have been reported in our group. As an asymmetric version
few examples have shown that the N–N bond of 4 could be utilized
for the synthesis of cyclic hydrazine derivatives; however, they are
limited only to 6-membered piperizine derivatives, where the
cyclization step involves either intramolecular alkylation reaction8
or Wittig reaction.9
of these methodologies, we envisioned that organocatalytic
a-
hydrazidination reaction followed by RCM could be synthetically
useful for enantioselective synthesis of functionalized cyclic
hydrazines.
Herein, we report indium-promoted one-pot allylation of 4 and
enantioselective synthesis of cyclic hydrazines (II) via an organo-
First, we examined the feasibility of the one-pot
allylation sequence. After treating aldehydes with 10 mol % of
-proline and dibenzyl diazodicarboxylate (CbzN@NCbz, 3) in
a-amination–
catalytic a-amination–allylation-RCM strategy. Synthetic methods
L
for small to medium heterocycles containing an N–O10 or N–N11
acetonitrile at ꢀ20 °C for 12 h, the reaction mixture was diluted
with THF/H2O (3:1) and then reacted with indium powder and allyl
bromide at room temperature for 12 h (Table 1). The overall
transformation turned out to be highly enantioselective and
* Corresponding author. Tel.: +82 2 2123 2603; fax: +82 2 364 7050.
E-mail address: jstae@yonsei.ac.kr (J. Tae).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.004

A. Lim et al. / Tetrahedron Letters 49 (2008) 4882–4885
4883
Table 1
One-pot proline-catalyzed
O
1. NaBH4
a-amination and indium-promoted allylation reactions
EtOH
N
HN
O
4d
OH
In (2eq)
Br
2 (10 mol %)
3 (1.2 eq)
2. K2CO3
toluene
R
Cbz
(2 eq)
6
1a-d
4a-d
CbzN NHCbz
(63% from 1d)
CH3CN (0.1 M)
-20 ºC, 12 h
CH3CN-THF-H2O
(4:3:1)
5a-d
NaH, DMF
CH2Br
NaH, DMF
NaH
r.t. 12 h
H2C=CHCH2Br
CH2Cl2
COCl
Entry
1
5
% Yield
dr (anti:syn)
% eea (anti/syn)
O
O
O
1
2
3
4
1a (R = Me)
1b (R = i-Pr)
1c (R = n-Bu)
5a (70)
5b (88)
5c (67)
5d (83)
>99:1
98:2
81:19
87:13
99/(—)b
98/(—)b
99/>98c
98/>98c
N
N
O
N
N
N
N
O
O
Cbz
Cbz
Cbz
1d (R = (CH2)2CH@CH2)
O
a
The
% ee’s were determined using Chiralcel OD-H column (1% i-PrOH in
8a (90%)
8b (85%)
8c (87%)
hexanes).
b
The % ee’s for the syn isomers of 5a and 5b were not determined.
The minor enantiomers of the syn isomers of 5c and 5d were not observed.
c
TBSO
R
1. TBSOTf
CH2Cl2
7a (76%)
7b (90%)
7c (82%)
7d (90%)
2,6-lutidine
5a-d
diastereoselective. When R is small (R = Me, entry 1, Table 1),
complete diastereoselective allylation is observed, but relatively
bulky R groups show decreased diastereoselectivities (entries 3
and 4, Table 1).
The stereochemistries of the allylation step are determined
after conversion of 5 to 1,3-oxazolidin-2-ones where the 1H NMR
chemical shifts of the methine protons12 were compared with
the known compounds.13 According to the assigned stereochemist-
ries of 5, the indium-promoted allylation step proceeds through
the Felkin–Ahn transition state (Fig. 1). It seems that the sterically
bulky –NCbzNHCbz group prevents chelation of the allylindium
reagent to give the Cram product.14
N
2. NaH, DMF
Cbz
N
H2C=CHCH2Br
Cbz
Scheme 2. Synthesis of RCM substrates from
L
-proline-catalyzed
a
-amination
adducts.
2. Experimental procedures
2.1. General procedure for the organocatalytic
allylation reaction
a-amination–
Next, the RCM substrates were prepared according to the
known procedures (Scheme 2). The dienes 8a–c were prepared
using standard alkylation or acylation conditions10,11 from 6,
which was synthesized from aldehyde 4d in 63% yield. Substrates
7a–d were prepared from 5a–d in two steps.
To a mixture of 1a (100 mg, 1.72 mmol) and L-proline (18 mg,
0.17 mmol) in acetonitrile (17 mL) was added the dibenzyl azodi-
carboxylate (616 mg, 2.07 mmol) and the reaction mixture was
stirred for 12 h at ꢀ20 °C. The reaction mixture was diluted with
17 mL of THF/H2O (3:1) and indium powder (ꢀ100 mesh indium
powder purchased from Aldrich; 395 mg, 3.44 mmol) and allyl bro-
mide (2.99 mL, 3.44 mmol) were added. The reaction mixture was
stirred for 12 h at room temperature, quenched with saturated 2 N
HCl (10 mL), extracted with EtOAc (10 mL ꢁ 3). The combined
organic solutions were dried over anhydrous MgSO4, and the resi-
due was chromatographed on silica gel (hexanes/EtOAc = 2:1) to
The substrates 7a–d and 8a–c were reacted with 10 mol %
Grubbs’ catalysts (11 or 12) under refluxing dichloromethane or
toluene solution (0.02 M) (Table 2). Sterically bulky substrate
(entry 2) and less reactive acryl amide substrate (entry 6) were
reacted using 2nd-generation catalyst (12). Cyclization yields are
good for most substrates to give 8-membered cyclic hydrazine
compounds. The triene substrate 7d yielded 7-membered product
13d only instead of the corresponding 8-membered cyclic hydr-
azine (entry 4). Facile ring-closure to cycloheptene rings was
further confirmed from the reaction of substrates 9 and 10, which
were prepared from 5d (Scheme 3). Under the condition A, 9
produced functionalized cycloheptene 13h in 85% yield in less than
2 h (entry 8). Interestingly, the dieneyne 10 gave only the diene-
RCM product 13i with no enyne-RCM products (entry 9).
In conclusion, we have shown that the indium-promoted in situ
give 5a (479 mg, 70%) as
a
ꢂ
white solid; Rf = 0.4 (hexanes/
EtOAc = 2:1); mp 74–76 °C; ½a D20
+2.28 (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.32–7.25 (m, 10H), 6.71(br s, 1H), 5.80 (br s,
1H), 5.14–5.08 (m, 7H), 4.19–3.99 (m, 2H), 2.20 (m, 2H), 1.15–
1.14 (d, J = 6.8 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) d 156.6,
155.8, 135.8, 135.6, 135.4, 134.8, 128.6, 128.5, 128.4, 127.9,
117.5, 72.4, 68.8, 68.1, 67.9, 57.8, 57.0, 38.1, 29.7, 9.9, 0.0; IR (film,
cmꢀ1) 3292, 3062, 3030, 2935, 2355, 1712, 1528, 1498, 1454, 1408,
1262, 1056, 1027; HRMS calcd for C22H26N2O5 (M+): 398.1842;
found: 398.1840.
allylation of organocatalytic a-amination adducts could introduce
1,2-aminoalcohols with high enantio- and diastereoselectivities.
In addition, we have demonstrated that functionalized cyclic
hydrazine derivatives could be readily accessed by using the
2.2. General procedure for the synthesis of RCM substrates 7
organocatalytic
a
-amination–allylation-RCM strategy.
To a solution of 5a (238 mg, 0.598 mmol) in CH2Cl2 (15 mL)
were added 2,6-lutidine (0.10 mL, 0.89 mmol) and TBSOTf
(0.20 mL, 0.89 mmol) at 0 °C under argon atmosphere. The result-
ing mixture was stirred at 0 °C for 20 min, warmed to room tem-
perature, and quenched with saturated aqueous NaHCO3. The
aqueous solution was extracted with CH2Cl2 (10 mL ꢁ 3) and the
combined organic solutions were dried over anhydrous MgSO4
and the residue was flash chromatographed on silica gel (hex-
anes/EtOAc = 10:1) to give TBS-protected compound. This product
was dissolved in DMF (15 mL) and treated with NaH (47 mg,
In
O
R
NHCbz
N
C
H
Cbz
H
Figure 1. A proposed transition state for the allylation reaction.

4884
A. Lim et al. / Tetrahedron Letters 49 (2008) 4882–4885
Table 2
RCM reactions of compounds 7–10
Entry
Substrate
Conditionsa
13
TBSO
Yieldb (%)
H3C
1
7a
A 4 h
92
N
Cbz
N
Cbz
13a
TBSO
2
7b
12 (10 mol %) toluene reflux, 6 h
88
N
Cbz
N
Cbz
13b
TBSO
3
7c
A 8 h
59
N
Cbz
N
Cbz
13c
TBSO
Cbz
Cbz
N
N
4
5
6
7d
8a
8b
A 2 h
66
85
82
13d
O
N
N
O
A 4 h
Cbz
13e
O
N
N
O
12 (10 mol %) CH2Cl2 reflux, 8 h
Cbz
O
13f
O
N
N
O
7
8
8c
A 4 h
75
Cbz
13g
O
N
O
9
A 2 h
85
23
Cbz NH
13h
TBSO
Cbz
Cbz
N
N
9
10
A 2 h
13i
a
Condition A: 11 (10 mol %), CH2Cl2, reflux, argon.
Mes-N
Cl
N-Mes
Cl
PCy3
Cl
Ru
12
Ru
11
Ph
Cl
Ph
PCy3
PCy3
b
Isolated yields.

A. Lim et al. / Tetrahedron Letters 49 (2008) 4882–4885
4885
thanks Yonsei University and Professor K.W.J. at USC for the sup-
ports during the sabbatical year.
5d
1. TBSOTf, CH2Cl2
2,6-lutidine
K2CO3
toluene
2. NaH
DMF
Supplementary data
CH2Br
The 1H NMR copies of 1,3-oxazolidin-2-ones 14 (see Ref. 12)
showing diastereomeric ratios are available. Supplementary data
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.06.004.
TBSO
O
N
O
Cbz
Cbz
N
N
Cbz NH
9 (85%)
10 (83%)
References and notes
Scheme 3. Synthesis of RCM substrates 9 and 10.
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1.2 mmol) followed by allyl bromide (0.10 mL, 1.2 mmol) at 0 °C.
The solution was stirred for 30 min at 0 °C and warmed to room
temperature for 2.5 h. The reaction mixture was quenched with
saturated aqueous NH4Cl (20 mL), extracted with CH2Cl2
(10 mL ꢁ 3). The combined organic solutions were dried over
anhydrous MgSO4 and the residue was chromatographed on silica
gel (hexanes/EtOAc = 6:1) to give 7a (250 mg, 76%) as a colorless
oil; Rf = 0.4 (silica gel, hexanes/EtOAc = 6:1); ½a D20
ꢂ
+7.33 (c 1.00,
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.29–7.23 (m, 10H), 5.89 (m,
1H), 5.26–4.91 (m, 9H), 4.19–3.85 (m, 2H), 2.45–2.03 (m, 2H),
1.25–0.86 (m, 14H), 0.05–0.00 (m, 5H); 13C NMR (62.9 MHz, CDCl3)
d 156.9, 156.4, 135.9, 135.8, 134.4, 133.5, 128.5, 128.2, 128.0,
127.9, 117.4, 72.4, 68.2, 67.9, 67.7, 59.8, 58.7, 56.5, 56.3, 56.0,
7. Zhong, G. Chem. Commun. 2004, 606–607.
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Asymmetry 2004, 15, 3477–3481; (b) Chandrasekhar, S.; Parimala, G.; Tiwari,
B.; Narsihmulu, C.; Sarma, G. D. Synthesis 2007, 1677–1682.
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2552.
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39.2, 38.7, 26.0 18.1, 15.5, 11.6, ꢀ3.8, ꢀ4.1, ꢀ4.3; IR (film, cmꢀ1
)
2954, 2919, 2848, 1714, 1454, 1399, 1301, 1223, 1145, 1086,
1043, 914; HRMS calcd for C31H44N2O5Si (M+): 552.3020; found:
552.3021.
2.3. General procedure for the RCM reaction
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Lee, D. Org. Lett. 2004, 6, 4351–4354.
A
mixture of 7a (135 mg, 0.240 mmol) and 11 (16 mg,
12. The diastereomeric ratios were determined after conversion of
5 to 1,3-
0.024 mmol) in CH2Cl2 (12 mL) was refluxed for 4 h under argon.
After concentration of the solution in vacuo, the residue was chro-
matographed on silica gel (hexanes/EtOAc = 6:1) to give 13a
(115 mg, 92%) as a colorless oil; Rf = 0.3 (hexanes/EtOAc = 6:1);
oxazolidin-2-ones 14 (for the procedures of the cleavage of the N–N bond in
step 3, see: Baumann, T.; Vogt, H.; Bräse, S. Eur. J. Org. Chem. 2007, 266–282).
While the chemical shifts of Ha and Hb for cis-isomers in 14 appear at 3.5–
3.9 ppm and 4.5–4.7 ppm, respectively, those of trans-isomers appear at 3.2–
3.4 ppm and 4.2–4.3 ppm (see Ref. 13 and Supplementary data).
½
a 2D0 +8.71 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.45–7.32
ꢂ
(m, 10H), 6.05 (m, 2H), 5.30–5.12 (m, 4H), 4.53–4.32 (m, 2H),
3.70–3.80 (m, 1H), 3.22–3.20 (m, 1H), 2.33 (m, 2H) 1.75–1.15 (m,
3H), 0.96–0.91 (m, 9H), 0.18–0.06 (m, 6H); 13C NMR (62.9 MHz,
CDCl3) d 155.1, 154.1, 136.2, 136.0, 128.7, 128.6, 128.5, 128.2,
128.1, 128.0, 127.9, 127.7, 127.5, 126.4 68,1 67.2, 65.7, 43.8, 33.2,
25.8, 18.0, 15.0, ꢀ4.3, ꢀ4.4, ꢀ4.7, ꢀ4.8; IR (film, cmꢀ1) 2954,
2923, 2856, 1711, 1462, 1399, 1356, 1305, 1286, 1258 1231,
cis
trans
R
n
-Pr
1. K2CO3
2. H2, Pd/C
Ha
Hb
Ha
Hb
Ha
Hb
-
R
5
HN
O
Me 3.90 4.57
-
3. NaNO2
HCl-AcOH
i
-Pr 3.54 4.57 3.18 4.27
O
14
n
-Bu 3.72 4.59 3.42 4.18
13. (a) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S. Chem. Lett. 1987, 1531–
1534; (b) Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. J. Org. Chem. 1989, 54, 4398–
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Chem. 1997, 62, 4293–4301.
1106, 1086, 1027, 933; HRMS calcd for
547.2707; found: 547.2707.
C
29H40N2O5Si (M+):
Acknowledgments
This work was supported by the Center for Bioactive Molecular
Hybrids (MOST/KOSEF). A.L. thanks BK 21 program (KRF). J.T.