Titanocene(III) chloride mediated radical induced allylation of aldimines: Formal synthesis of C-linked 4′-deoxy aza-disaccharide

Article abstract of DOI:10.1021/jo200908b

Titanocene(III) chloride (Cp₂TiCl) mediated radical induced allylation of aldimines for the preparation of homoallyl amines is described. The radical was generated from the allyl bromide using Cp₂TiCl as the radical source. Formal synthesis of C(4)-C(5′)-linked 4′-deoxy aza-disaccharide is demonstrated and a study toward the bicyclic skeleton of alkaloids was also accomplished. The radical initiator Cp₂TiCl was prepared in situ from commercially available titanocene dichloride (Cp ₂TiCl₂) and Zn dust in THF under argon.

Full text of DOI:10.1021/jo200908b

NOTE
pubs.acs.org/joc
Titanocene(III) Chloride Mediated Radical Induced Allylation of
Aldimines: Formal Synthesis of C-Linked 40-Deoxy Aza-disaccharide
Sumit Saha and Subhas Chandra Roy*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
S Supporting Information
b
ABSTRACT: Titanocene(III) chloride (Cp2TiCl) mediated radical induced allylation
of aldimines for the preparation of homoallyl amines is described. The radical was
generated from the allyl bromide using Cp2TiCl as the radical source. Formal
synthesis of C(4)ꢀC(50)-linked 40-deoxy aza-disaccharide is demonstrated and a
study toward the bicyclic skeleton of alkaloids was also accomplished. The radical
initiator Cp2TiCl was prepared in situ from commercially available titanocene dichloride (Cp2TiCl2) and Zn dust in THF
under argon.
omoallyl amines are versatile intermediates for the prepara-
tion of widely used compounds for the synthesis of naturally
Scheme 1. Cp2TiCl Mediated Allylation of Aromatic
Aldimines
H
occurring targets such as β-amino acids or esters, 1,3-amino
alcohols, and 1-amino-3,4-epoxides.1,2 For instance, β-amino
acids used for the synthesis of β-lactam antibiotics such as
antimicrobial 1β-methyl carbapenem and R-branched amines,
e.g., cinacalcet, can also be obtained from homoallyl amines.3
Homoallyl amines proved to be eminent building units for the
asymmetric synthesis of pyrrolidines and piperidines via a ring-
closing metathesis (RCM).4 Moreover, it has also been assayed
that homoallyl amines containing aryl rings at C-4 of butene
moiety exhibit considerable antimicrobial activity against some
infective dermatophytes.5
The usual approach for the preparation of homoallyl amines
is a nucleophilic addition of allyl-metal compounds to aldimines
in the presence of a Lewis acid.6 There are also several other
methods for the synthesis involving metals in association with
ionic liquids, poly(ethylene glycol) (PEG) and some other metal
salts.7 Recently, Gall and his co-workers reported3b similar types
of reactions using only Zn metal but failed to produce allylated
products using Zn and allyl bromide. However, most of the
reported methods suffer from functional group intolerance,
substrate variation, and the use of expensive and toxic catalysts,
implying the need for a more efficient method especially in chiral
molecules. The mildness and efficiency of bis-cyclopentadienyl
titanocene(III) chloride (Cp2TiCl) mediated radical induced
reactions have significantly inspired synthetic chemists in recent
years to utilize radical technology in developing synthetic
strategy and its application in natural product synthesis.8 In
continuation of our studies for the synthesis of natural products
involving radical-induced reactions,9 we report here a mild and
efficient Cp2TiCl mediated radical induced synthesis of homo-
allyl amines. Titanocene(III) chloride (Cp2TiCl) was prepared
in situ from commercially available titanocene dichloride
(Cp2TiCl2) using Zn dust in THF.8a Thus, freshly prepared
Cp2TiCl in THF was added dropwise at room temperature to the
aldimine (prepared by mixing the aldehyde and amine under
vacuum) and allyl bromide, furnishing the homoallyl amines in
excellent yield. There are several one-pot strategies for the syn-
thesis of homoallylic amines reported in the literature where
most likely the reaction goes via the formation of imines as an
intermediate.10 In a preliminary experiment, Cp2TiCl in THF
was added dropwise to the solution of phenyl aldimine 1a in THF.
The resulting solution was stirred at room temperature for additional
2 h to furnish the allylated product 1b in 68% yield (Scheme 1). In
the 1H NMR spectrum of 1b, allylic methylene protons appeared at
δ 2.5 and the olefinic protons appeared at δ 5ꢀ6.
Thus, a series of aromatic aldimines were subjected to allyla-
tion reaction; the results are summarized in Table 1. When the
aromatic amine was replaced by a N-aliphatic amine (Table 1,
1
entry 11), a trace amount of product was observed in the H
NMR. This indicates that although the allylic titanocene would
act as reactive species generated via one-electron transfer process,
the subsequent allylation step to imine might go through an ionic
process (Scheme 2) stabilized by the adjacent aromatic ring.
Next, some chiral aldimines were subjected to allylation
reaction; the results are summarized in Table 2. The correspond-
ing desired homoallyl amines were isolated with better yield
compared to the aromatic aldimines. The optically pure aldi-
mines (Table 2, entry 13ꢀ17) yielded a mixture of isomers,
although the formation of one isomer was found to dominate.
Only two isomers of 17b could be separated by chromatographic
methods, but the structures of the two isomers 17b1 (major) and
17b2 (minor) were confirmed in the later stage. Isomers in the
Received: May 6, 2011
Published: July 27, 2011
r
2011 American Chemical Society
7229
dx.doi.org/10.1021/jo200908b J. Org. Chem. 2011, 76, 7229–7234
|

The Journal of Organic Chemistry
NOTE
Table 1. Cp2TiCl Mediated Allylation of Aromatic Aldimines
Table 2. Cp2TiCl Mediated Allylation of Chiral Aldimines
entry
R1
R2
C6H5
yield (%)a
ref
1
C6H5
C6H5
C6H5
C6H5
C6H5
68
62
65
64
65
65
64
65
60
63
tr
6b
6f
2
4-MeO-C6H4
4-Cl-C6H4
1-naphthyl
4-Me-C6H4
C6H5
3
6b
6b
6b
6b
6b
6b
6f
4
5
6
4-Me-C6H4
4-Cl-C6H4
4-MeO-C6H4
2-naphthyl
2-OH-C6H4
C6H5
7
C6H5
8
C6H5
9
C6H5
10
C6H5
6f
11
PhCH2
a Isolated yield.
Scheme 2. Plausible Reaction Pathway of Allylation
a Isolated yield. b Distereomeric ratio determined by GC. c PMP =
4-methoxy phenyl.
of the benzene ring (anisotropic effect). As a result, the methoxy
protons of the cyclic amide 17d appeared at δ 2.46, whereas the
same protons appeared at δ 3.27 for the acyclic amide 17c. So, by
analogy with the X-ray structure of 17d, assignment of stereo-
chemistry of the major isomer of homoallyl amine 17b1 as shown
in Scheme 3 could easily be determined.
Compound 15b was converted to the cyclic amide 15d through
acylation followed by RCM (Scheme 4). It is expected that com-
pound 15d could easily be converted to bicyclic skeletons16 related
to alkaloids through some classical transformations as shown in
Scheme 4, which is under progress and will be reported elsewhere.
In conclusion, we have demonstrated a titanocene(III) chloride
mediated radical induced mild and convenient allylation of
aldimines and its application toward the synthesis of some
important aza-sugar molecules and alkaloid skeletons.
other compounds 13bꢀ16b could not be separated by usual
chromatographic methods.
The better diastereoselectivity observed for compounds 13bꢀ17b
at room temperature compared to reported literature11 encour-
aged us to apply the methodology to the synthesis of heterocyclic
natural products and related compounds. Aza-sugars are impor-
tant analogues in sugar chemistry, and their inhibitory activity12
against glycosidases or glycosyl transferases are well-known. There
are several reports on the synthesis of aza-sugar derivatives,11 but
still advancement is required for a better stereoselective synthetic
protocol with fewer number of steps and satisfactory yield.
To focus this idea, the major isomer of homo allyl amine 17b1
was acylated13 with acryloyl chloride in the presence of Et3N
to afford the acylated product 17c. Finally, compound 17c
was subjected to RCM14 using second generation Grubbs catalyst to
obtain the cyclic amide 17d (Scheme 3). The 4-methoxy phenyl
group in compound 17d was deprotected15 by CAN in aqueous
CH3CN to furnish compound 17e. Compound 17e has already been
transformed to C(4)ꢀC(50)-linked 40-deoxy aza-D-disaccharide 17f
in one step.12a So, we report here a formal synthesis of C(4)ꢀC-
(50)-linked 40-deoxy aza-D-disaccharide 17f.
’ EXPERIMENTAL SECTION
Representative Procedure for the Preparation of Aldi-
mine 1a. Benzaldehyde (106 mg, 1 mmol) and aniline (93 mg, 1
mmol) were mixed in a small round-bottom flask. The crude oil was left
under vacuum (4 ꢁ 10ꢀ4 mbar) for 10 min, until all of the oil was
solidified. The crude solid aldimine 1a (170 mg, 90%) was subjected to
allylation reaction without further purification.
All other aldimines 2aꢀ17a were prepared following the same
The structure of the compound 17d was confirmed by X-ray
crystallographic study (Figure 1). The three-dimensional X-ray
structure of 17d showed that the methyl protons of the methoxy
group attached to the furanose ring came into the shielding zone
procedure as stated above for 1a.
Representative Procedure for Cp2TiCl Mediated Allylation
of Aldimine 1a: Preparation of Phenyl-(1-phenyl-but-3-enyl)-
amine (1b). A solution of titanocene dichloride (370 mg, 1.5 mmol)
7230
dx.doi.org/10.1021/jo200908b |J. Org. Chem. 2011, 76, 7229–7234

The Journal of Organic Chemistry
NOTE
Scheme 3. Formal Synthesis of Deoxy Aza-disaccharide
60 mL of 4 M HCl and thorough washing with water and finally with
dry acetone and then drying in vacuo). The resulting green solution was
then added dropwise to a stirred solution of the aldimine 1a (140 mg,
0.75 mmol) and allyl bromide (1.5 equiv) in dry THF (25 mL per mmol
of compound) at room temperature under argon during 1 h. The
reaction mixture was further stirred for 2 h. After completion of
the reaction (monitored by TLC) the mixture was quenched with
10% aqueous Na2HPO4 until complete precipitation. Most of the
solvent was removed under reduced pressure, and the residue was
extracted with diethyl ether (4 ꢁ 30 mL). The combined ether extract
was washed with water (10 mL) and brine (10 mL) and finally dried
(Na2SO4). After removal of the solvent the crude residue obtained was
purified by column chromatography over silica gel (10% ethyl acetate in
light petroleum) to afford phenyl-(1-phenyl-but-3-enyl)-amine (1b) as a
viscous liquid in 68%yield. IR (neat): 3053, 2978, 2931, 1600, 1506 cmꢀ1
.
Figure 1. X-ray structure of 17d.
1H NMR (300 MHz, CDCl3): δ 2.35ꢀ2.54 (m, 2H), 4.29 (t, J = 6.0 Hz,
1H), 5.03ꢀ5.12 (m, 2H), 5.60ꢀ5.71 (m, 1H), 6.39ꢀ6.41 (m, 2H),
6.53ꢀ6.57 (m, 1H), 6.96ꢀ7.00 (m, 2H), 7.12ꢀ7.15 (m, 1H), 7.15ꢀ7.28
(m, 4H); 13C NMR (75 MHz, CDCl3): δ 43.4, 57.3, 113.6, 117.5, 118.4,
126.4, 127.1, 128.7, 129.2, 134.7, 134.8, 143.6, 147.4.
Scheme 4. Synthesis toward Bicyclic Skeleton of Alkaloids
(4-Methoxy-phenyl)-(1-phenyl-but-3-enyl)-amine (2b). IR
(neat): 3400, 3061, 2931, 1514, 1240, 1037 cmꢀ1; 1H NMR (300 MHz,
CDCl3): δ 2.46ꢀ2.65 (m, 2H), 3.72 (s, 3H), 4.33ꢀ4.35 (m, 1H),
5.16ꢀ5.24 (m, 2H), 5.74ꢀ5.85 (m, 1H), 6.50 (d, J = 7.5 Hz, 2H), 6.72
(d, J = 7.5 Hz, 2H), 7.27ꢀ7.41 (m, 5H). 13C NMR (75 MHz, CDCl3):
δ 43.5, 55.8, 58.1, 114.8, 118.3, 118.3, 126.5, 127.0, 128.7, 134.9, 141.7,
143.9, 152.1.
(4-Chloro-phenyl)-(1-phenyl-but-3-enyl)-amine (3b). IR
(neat): 3390, 3050, 2920, 1530, 1250, 1040 cmꢀ1 1H NMR (500
.
MHz, CDCl3): δ 2.47ꢀ2.53 (m, 1H), 2.60ꢀ2.64 (m, 1H), 4.35 (dd,
J = 5.0, 8.0 Hz, 1H), 5.16ꢀ5.21 (m, 2H), 5.73ꢀ5.80 (m, 1H), 6.40ꢀ6.43
(m, 2H), 7.00ꢀ7.04 (m, 2H), 7.31ꢀ7.32 (m, 5H). 13C NMR (125
MHz, CDCl3): δ 43.3, 57.4, 114.8, 118.6, 126.4, 127.3, 128.8, 129.0,
134.5, 143.0, 145.9.
Naphthalen-1-yl-(1-phenyl-but-3-enyl)-amine(4b).IR(neat):
3410, 3043, 2920, 1510, 1320,1250 cmꢀ1. 1H NMR (300 MHz, CDCl3):
δ 2.63ꢀ2.84 (m, 2H), 4. 60 (dd, J = 5.0, 7.8 Hz, 1H), 5.25ꢀ5.39 (m, 2H),
5.81ꢀ5.95 (m, 1H), 7.20ꢀ7.40 (m, 3H), 7.48ꢀ7.59 (m, 6H), 7.68ꢀ7.90
(m, 3H). 13C NMR (75 MHz, CDCl3): δ 43.7, 57.0, 106.3, 117.4, 118.8,
119.9, 123.6, 124.9, 125.8, 126.7, 128.8, 128.9, 129.0, 134.4, 135.0,
142.2, 143.3.
(1-Phenyl-but-3-enyl)-p-tolyl-amine (5b). IR (neat): 3410,
in dry THF (25 mL per mmol of reagent) was stirred with activated zinc
dust (250 mg, 3.75 mmol) for 1 h under argon (activated zinc dust
was prepared by washing 20 g of commercially available zinc dust with
3026, 2916, 1519, 1301, 1265, 1040 cmꢀ1 1H NMR (500 MHz,
.
CDCl3): δ 2.22 (s, 3H), 2.51ꢀ2.56 (m, 1H), 2.63ꢀ2.66 (m, 1H),
4.40 (dd, J = 5.0, 8.0 Hz, 1H), 5.17ꢀ5.24 (m, 2H), 5.76ꢀ5.81 (m, 1H),
7231
dx.doi.org/10.1021/jo200908b |J. Org. Chem. 2011, 76, 7229–7234

The Journal of Organic Chemistry
NOTE
6.45ꢀ6.48 (m, 2H), 6.92ꢀ6.94 (m, 2H), 7.34ꢀ7.41 (m, 5H). 13C NMR
(125 MHz, CDCl3): δ 20.4, 43.4, 57.6. 113.7, 118.3, 126.4, 126.6, 127.0,
128.7, 129.1, 129.7, 134.9, 143.9, 145.2.
[1-(1,4-Dioxa-spiro[4.5]dec-2-yl)-but-3-enyl]-(4-methoxy-
phenyl)-amine (15b). IR (neat): 3400, 2936, 2862, 1512, 1236,
1
1099 cmꢀ1. H NMR (300 MHz, CDCl3): δ 1.26ꢀ1.40 (m, 2H),
1.59ꢀ1.65 (m, 8H), 2.33ꢀ2.40 (m, 2H), 3.35ꢀ3.42 (m, 1H), 3.74 (s,
3H), 3.83ꢀ3.95 (m, 1H), 3.97ꢀ4.05 (m, 2H), 5.06ꢀ5.14 (m, 2H),
5.81ꢀ5.90 (m, 1H), 6.57ꢀ6.62 (m, 2H), 6.75ꢀ6.78 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 23.1, 23.9, 25.3, 34.8, 36.7, 54.7, 55.8, 56.8, 66.1,
109.8, 110.0, 115.0, 115.6, 117.7, 118.3, 134.4, 134.5, 135.1, 141.6.
HRMS: calcd for C19H28NO3 [M + H+] 318.2069; found 318.2065.
[1-(6-Methoxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]-
dioxol-5-yl)-but-3-enyl]-phenyl-amine (16b). IR (neat): 3387,
3055, 2985, 2937, 1602, 1498, 1438, 1373 cmꢀ1. 1H NMR (500 MHz,
CDCl3): δ 1.33 (s, 3H), 1.45 (s, 3H), 2.42ꢀ2.49 (m, 2H), 3.27 (s, 3H),
3.71 (s, 1H), 3.99ꢀ4.01 (m, 2H), 4.55 (d, J = 4.0 Hz, 1H), 5.10
(m, 2H), 5.83ꢀ5.87 (m, 1H), 5.91 (d, J = 3.5 Hz, 1H), 6.67ꢀ6.70
(m, 3H), 7.13ꢀ7.16 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 26.4,
27.0, 50.9, 57.7, 81.5, 81.6, 83.8, 105.1, 111.7, 114.3, 117.7, 118.6,
129.3, 134.2, 147.6. HRMS: calcd for C18H26NO4 [M + H+] 320.1862;
found 320.1875.
[1-(6-Methoxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1,3]-
dioxol-5-yl)-but-3-enyl]-(4-methoxy-phenyl)-amine (17b1,
major isomer). IR (neat): 3385, 3052, 2985, 2937, 1602, 1490,
1431, 1370 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 1.30 (s, 3H), 1.49
(s, 3H), 2.37ꢀ2.49 (m, 2H), 3.27 (s, 3H), 3.71ꢀ3.72 (m, 1H), 3.74
(s, 3H), 3.86ꢀ3.90 (m, 1H), 3.96 (dd, J = 3.0, 9.0 Hz, 1H), 4.55 (d, J =
3.5 Hz, 1H), 5.09ꢀ5.12 (m, 2H), 5.81ꢀ5.84 (m, 1H), 5.87 (d, J = 2.5
Hz, 1H), 6.63 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H). 13C NMR
(125 MHz, CDCl3): δ 12.3, 14.3, 36.3, 51.9, 55.9, 57.8, 81.2, 817, 83.7,
105.1, 111.7, 114.9, 115.8, 118.6, 134.2. HRMS calcd for C19H28NO5
[M + H+] 350.1967; found 350.1962.
Preparation of N-[1-(6-Methoxy-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)-but-3-enyl]-N-(4-methoxy-phenyl)-
acrylamide (17c). To a stirred solution of the homoallyl amine 17b1
(350 mg, 1 mmol) and Et3N (0.2 mL, 1.5 mmol) in DCM (2 mL) was
added acryloyl chloride (120 mg, 1.3 mmol) in DCM (2 mL) at 0 °C.
The reaction mixture was stirred for 1 h at this temperature and then
at room temperature for 3 h. Then the reaction mixture was quenched
with saturated NaHCO3 solution (10 mL) and extracted with DCM
(3 ꢁ 30 mL). The combined organic layer was washed with water
(3 ꢁ 10 mL) and brine (5 mL) and finally dried over Na2SO4. The sol-
vent was evaporated under reduced pressure, and crude product ab-
tained was subjected to column chromatography to furnish the desired
acetylated product 17c (330 mg, 80%) as a colorless liquid. IR (neat):
3074, 2985, 2935, 2835, 1735, 1647, 1510, 1408 cmꢀ1. 1H NMR (500
MHz, CDCl3): 1.23 (s, 3H), 1.45 (s, 3H), 2.61ꢀ2.74 (m, 2H), 3.27
(s, 3H), 3.72ꢀ3.75 (m, 1H), 3.81 (s, 3H), 4.39ꢀ4.44 (m, 1H), 4.52 (d,
J = 4.0 Hz, 1H), 5.04ꢀ5.09 (m, 2H), 5.44 (dd, J = 1.5, 10.5 Hz, 1H),
5.82ꢀ5.91 (m, 3H), 6.28 (dd, J = 1.5, 17.0 Hz, 1H), 6.86 (d, J = 9.0 Hz,
2H), 7.10 (d, J = 8.5 Hz, 2H). 13C NMR (125 MHz, CDCl3): δ 26.4,
26.9, 33.6, 55.6, 57.6, 80.7, 81.4, 84.4, 104.8, 111.7, 114.3, 116.9, 127.3,
129.8, 136.2, 159.1, 166.7. HRMS: calcd for C22H29NO6Na [M + Na+]
426.1893; found 426.1893.
Preparation of 6-(6-Methoxy-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)-1-(4-methoxy-phenyl)-5,6-dihydro-
1H-pyridin-2-one (17d). The second generation Grubbs catalyst (37 mg,
5 mol %) was added to a solution of 17c (320 mg, 0.80 mmol) in CH2Cl2
(20 mL) under an Ar atmosphere. After being stirred under reflux for 5 h, the
resulting solution was exposed to air with stirring for 1 h, concentrated, and
purified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 3:2) to give cyclic amide 17d (210 mg, 70%) as a colorless
crystalline solid. IR (KBr): 2924, 1662, 1512, 1246, 1078 cmꢀ1. 1H NMR
(500 Mz, CDCl3): δ 1.22 (s, 3H), 1.41 (s, 3H), 2.46 (s, 3H), 2.71ꢀ2.78 (m,
2H), 3.34 (d, J = 2.5 Hz, 1H), 3.72 (s, 3H), 4.24 (dd, J = 2.5, 9.5 Hz, 1H),
4.37 (d, J = 3.5 Hz, 1H), 4.40ꢀ4.43 (m, 1H), 5.66 (d, J = 4.0 Hz, 1H), 6.01
Phenyl-(1-p-tolyl-but-3-enyl)-amine (6b). IR (neat): 3406,
3051, 2920, 1504, 1305, 1267, 1168 cmꢀ1 1H NMR (500 MHz,
.
CDCl3): δ 2.23 (s, 3H), 2.37ꢀ2.43 (m, 1H), 2.49ꢀ2.52 (m, 1H),
4.26ꢀ4.27 (m, 1H), 5.03ꢀ5.10 (m, 2H), 5.63ꢀ5.71 (m, 1H),
6.41ꢀ6.42 (m, 2H), 6.54ꢀ6.56 (m, 1H), 6.97ꢀ7.04 (m, 4H),
7.13ꢀ7.23 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 21.2, 43.4,
57.1, 113.7, 117.5, 118.2, 129.2, 129.4, 129.8, 130.0, 134.9, 136.6.
[1-(4-Chloro-phenyl)-but-3-enyl]-phenyl-amine (7b). IR
1
(neat): 3412, 3051, 2910, 1505, 1315, 1205, 1089 cmꢀ1. H NMR
(500 MHz, CDCl3): δ 2.37ꢀ2.43 (m, 1H), 2.48ꢀ2.53 (m, 1H), 4.27
(dd, J = 5.5, 8.0 Hz, 1H), 5.06ꢀ5.11 (m, 2H), 5.60ꢀ5.66 (m, 1H),
6.39ꢀ6.40 (m, 2H), 6.58ꢀ6.61 (m, 1H), 6.99ꢀ7.02 (m, 2H),
7.20ꢀ7.23 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 43.2, 57.0,
113.9, 118.8, 127.9, 128.9, 129.3, 129.6, 130.1, 131.0, 132.8, 134.3.
[1-(4-Methoxy-phenyl)-but-3-enyl]-phenyl-amine (8b). IR
(neat): 3410, 3051, 2906, 2835, 1506, 1246, 1033 cmꢀ1. 1H NMR (500
MHz, CDCl3): δ 2.40ꢀ2.44 (m, 1H), 2.48ꢀ2.52 (m, 1H), 3.70 (s, 3H),
4.26 (dd, J = 5.5, 7.5 Hz, 1H), 5.04ꢀ5.10 (m, 2H), 5.64ꢀ5.70 (m, 1H),
6.42 (d, J = 8.5 Hz, 2H), 6.56 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 8.5 Hz, 2H),
6.98ꢀ67.01 (m, 2H), 7.06ꢀ7.20 (d, J = 11.5 Hz, 2H). 13C NMR (125
MHz, CDCl3): δ 43.4, 55.4, 57.0, 113.8, 114.1, 117.7, 118.3, 127.5,
129.2, 134.9, 147.4, 158.8.
(1-Naphthalen-2-yl-but-3-enyl)-phenyl-amine (9b). IR(neat):
3412, 3051, 2910, 1507, 1313,1271 cmꢀ1. 1H NMR (500 MHz, CDCl3):
δ 2.54ꢀ2.76 (m, 2H), 4.56 (dd, J = 5.5, 8.0 Hz, 1H), 5.16ꢀ5.24 (m, 2H),
5.76ꢀ5.80 (m, 1H), 6.58ꢀ6.60 (m, 2H), 6.66ꢀ6.69 (m, 1H), 7.07ꢀ7.10
(m, 2H), 7.31ꢀ7.49 (m, 3H), 7.67ꢀ7.84 (m, 4H). 13C NMR (125 MHz,
CDCl3): δ 29.9, 57.9, 114.1, 118.6, 124.8, 125.3, 125.7, 126.2, 127.8, 128.0,
128.8, 129.7, 133.0, 133.7, 135.2.
2-(1-Phenylamino-but-3-enyl)-phenol (10b). IR (neat):
3400, 3335, 3057, 2933, 2858, 1573, 1485, 1352, 1280, 1230, 1186 cmꢀ1
.
1H NMR (500 MHz, CDCl3): δ 2.67ꢀ2.70 (m, 2H), 4.33 (t, J = 7.0 Hz,
1H), 5.27ꢀ5.30 (m, 2H), 5.82ꢀ5.87 (m, 1H), 6.77ꢀ6.78 (m, 2H),
6.82ꢀ6.84 (m, 1H), 6.89ꢀ6.92 (m, 2H), 7.14ꢀ7.18 (m, 4H). 13C NMR
(125 MHz, CDCl3): δ 41.5, 60.1, 116.9, 117.3, 119.8, 120.2, 127.9, 128.7,
129.4, 134.4, 156.7.
(1-Allyl-2-prop-2-ynyloxy-pent-4-enyl)-phenyl-amine (12b).
IR (neat): 3304, 3076, 2976, 2926, 2247, 1600, 1506, 1259, 1082 cmꢀ1
.
1H NMR (300 MHz, CDCl3): δ 2.21ꢀ2.30 (m, 3H including the
acetylinic proton), 2.32ꢀ2.41 (m, 2H), 3.44ꢀ3.50 (m, 1H), 3.60ꢀ
3.66 (m, 1H), 4.08 (dd, J = 2.3, 18.2 Hz, 1H), 4.20 (dd, J = 2.5, 15.9 Hz,
1H), 4.93ꢀ5.16 (m, 4H), 5.72ꢀ5.87 (m, 2H), 6.49ꢀ6.67 (m, 2H),
7.05ꢀ7.15 (m, 2H), 7.17ꢀ7.19 (m, 1H). 13C NMR (75 MHz, CDCl3):
δ 33.9, 35.7, 54.9, 57.9, 74.5, 79.7, 80.3, 113.6, 117.4, 118.0, 129.0,
134.3, 135.7, 147.7. HRMS: calcd for C17H22NO [M + H+] 256.1701;
found 256.1719.
2-(1-Phenylamino-but-3-enyl)-pyrrolidine-1-carboxylic Acid
tert-Butyl Ester (13b). IR (neat): 3365, 2972, 2926, 2854, 1672, 1600,
1
1396, 1317, 1165 cmꢀ1. H NMR (500 MHz, CDCl3): δ 1.35ꢀ1.65
(m, 9H), 1.74ꢀ1.86 (m, 4H), 2.10ꢀ2.38 (m, 2H), 2.85ꢀ3.60 (m, 2H),
3.70ꢀ3.9 (m, 1H), 4.02ꢀ4.06 (m, 1H), 4.95ꢀ5.03 (m, 2H), 5.74ꢀ5.80
(m, 1H), 6.49ꢀ6.61 (m, 3H), 7.01ꢀ7.06 (m, 2H). HRMS: calcd for
C19H28N2O2Na [M + Na+] 339.2048; found 339.2048.
2,2-Dimethyl-4-(1-phenylamino-but-3-enyl)-oxazolidine-
3-carboxylic Acid tert-Butyl Ester (14b). IR (neat): 3404, 3055,
2978, 2933, 1693, 1602, 1498, 1392, 1367, 1257, 1172 cmꢀ1. 1H NMR
(500 MHz, CDCl3): δ 1.33ꢀ1.45 (m, 15H), 2.06ꢀ2.43 (m, 2H), 3.73ꢀ
3.89 (m, 1H), 3.90ꢀ4.02 (m, 1H), 4.03ꢀ4.07 (m, 1H), 4.15ꢀ4.18 (m,
1H), 4.97ꢀ5.08 (m, 2H), 5.77ꢀ5.79 (m, 1H), 6.48ꢀ6.61 (m, 3H),
7.05ꢀ7.08 (m, 2H). HRMS: calcd for C20H30N2O3Na [M + Na+]
369.2154; found 369.2155.
7232
dx.doi.org/10.1021/jo200908b |J. Org. Chem. 2011, 76, 7229–7234

The Journal of Organic Chemistry
NOTE
(dd, J = 2.5, 8.0 Hz, 1H), 6.54ꢀ6.57 (m, 1H), 6.83ꢀ6.86 (m, 2H),
7.20ꢀ7.22 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 26.2, 26.3, 26.9,
55.2, 55.7, 56.2, 78.0, 81.3, 82.2, 104.3, 112.1, 114.1, 125.6, 128.0, 134.4, 138.
Crystallographic data including CIF file of compound 17d.
This material is available free of charge via the Internet at http://
pubs.acs.org.
9, 157.9, 163.4. [R]27.0 = 7.95 (c 1.12 in CHCl3). HRMS calcd for
D
C20H25NO6Na [M + Na]+ 398.1580; found 398.1581.
’ AUTHOR INFORMATION
Preparation of 6-(6-Methoxy-2,2-dimethyl-tetrahydro-
furo[2,3-d][1,3]dioxol-5-yl)-5,6-dihydro-1H-pyridin-2-one
(17e). A solution of 17d (190 mg, 0.5 mmol) in acetonitrile (2 mL)
was cooled to 0 °C. A solution of CAN (960 mg, 1.75 mmol) in water
(1 mL) was added to it dropwise at 0 °C. Then the reaction mixture
was stirred for 5 h at room temperature. The mixture was extracted
with ethyl acetate (3 ꢁ 30 mL). The combined organic extract was
washed with water (3 ꢁ 5 mL) and brine (10 mL) and finally dried
over Na2SO4. The crude product was subjected to column chroma-
tography to furnish the desired deprotected cyclic amide 17e (90 mg,
65%). [R]27.0D = ꢀ33.7 (c 0.02, CHCl3). IR (neat): 3212, 2953, 2854,
Corresponding Author
*E-mail: ocscr@.iacs.res.in.
’ ACKNOWLEDGMENT
We sincerely thank DST, New Delhi for financial support. S.S.
thanks CSIR, New Delhi for the award of a fellowship. We also
express our sincere thanks to Sayantan Paira, Inorganic Chem-
istry Department of this Institute.
1
1683, 1557, 1457, 1374 cmꢀ1. H NMR (500 Mz, CDCl3): δ 1.32
’ REFERENCES
(s, 3H), 1.47 (s, 3H), 2.63ꢀ2.68 (m, 2H), 3.45 (s, 3H), 3.83 (d, J = 3.5
Hz, 1H), 3.85ꢀ3.87 (m, 1H), 4.28 (dd, J = 3.5, 9.5 Hz, 1H), 4.63 (d,
J = 3.5 Hz, 1H), 5.87 (d, J = 4.0 Hz, 1H), 5.93ꢀ5.95 (m, 1H),
6.61ꢀ6.62 (m, 1H). HRMS: calcd for C13H19NO5Na [M + Na]+
292.1161; found 292.1161.
(1) (a) Laschat, S.; Kunz, H. J. Org. Chem. 1991, 56, 5883–5889.
(b) Graf, E.; Boeddeker, H. Liebigs Ann. Chem. 1958, 613, 111–120.
(c) Yoshioko, T.; Kuraoka, Y.; Tikita, T.; Maeda, K.; Umezawa, H.
J. Antibiot. 1972, 25, 625–626. (d) Wakamiya, T.; Shiba, T.; Kaneko, T.
Bull. Chem. Soc. Jpn. 1972, 45, 3668–3669.
(2) (a) Juaristi, E.; LeonꢀRomo, J. L.; Reyes, A.; Escalante, J.
Tetrahedron: Asymmetry 1999, 10, 2441. (b) Alvaro, G.; Savoia, D.
Tetrahedron: Asymmetry 1996, 7, 2083. (c) Moody, C. J.; Hunt, J. C.
Synlett 1998, 733. (d) Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J. Org.
Chem. 1990, 55, 215. (e) Laschat, S.; Kunz, H. Synlett. 1990, 51. (f) Hua,
D. H.; Miao, S. W. M.; Chen, J. S.; Iguchi, S. J. Org. Chem. 1991, 56, 4.
(3) (a) Hashihayata, T.; Sakoh, H.; Goto, Y.; Yamada, K.; Morishima,
H. Chem. Pharm. Bull. 2002, 3, 423. (b) Gall, E. L.; Haurena, C.;
Sengmany, S.; Martens, T.; Troupel, M. J. Org. Chem. 2009, 74, 7970.
(4) (a) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun.
2000, 1771. (b) Ovaa, H.; Stragies, R.; Marel, G. A. V.; Boom, J. H. V.;
Blechert, S. Chem. Commun 2000, 1501.
(5) (a) Barrio, A, G.; Pereira, D, M.; Ruiz, J. J. N.; Escario, J. A.;
Serrano, S. M.; Kouznetsov, V. V.; Mendez, L. Y. V.; Gonzales, J. M. U.;
Ochoa, C. Acta Parasitol. 2006, 51, 73. (b) Mendez, L. Y. V.; Zacchino,
S. A.; Kouznetsov, V. V. J. Braz. Chem. Soc. 2010, 21, 105.
(6) (a) Hatano, M.; Suzuki, S.; Ishihara, K. J. Am. Chem. Soc. 2006,
128, 9989. (b) Yuan, Y.; Chen, F.; Zhao, D. Appl. Organometal. Chem.
2009, 23, 485. (c) Wei, X. N.; Liu, L. Y.; Wang, B.; Chang, W. X.; Li
J. Chin. Chem. Lett. 2009, 20, 40. (d) Deng, D. S.; Liu, Ping.; Cai, J. Eur. J.
Org. Chem. 2007, 1594. (e) Yin, Y.; Zhao, G.; Li, G. L. Tetrahedron 2005,
61, 12042. (f) Zhengfeng, X.; Guilong, L.; Gang, Z.; Jide, W. Chin. J.
Chem. 2009, 27, 925.
(7) (a) Law, M. C.; Cheung, T. W.; Wong, K. Y.; Chan, T. H. J. Org.
Chem. 2007, 72, 923. (b) Shen, K. H.; Yao, C. F. J. Org. Chem. 2006,
71, 3980. (c) Andrews, P. C.; Peatt, A. C.; Raston, C. L. Green Chem.
2004, 6, 119. (d) Shibata, I.; Nose, K.; Sakamoto, K.; Yasuda, M.; Baba,
A. J. Org. Chem. 2004, 69, 2185. (e) Han, R.; Choi, S. H.; Son, K. I.; Jun,
Y. M.; Lee, B. M.; Kim, B. H. Synth. Commun. 2005, 35, 1725. (f) Shibata,
I.; Miyamoto, S.; Tsunoi, S.; Sakamoto, K.; Baba, A. Eur. J. Org. Chem.
2009, 3508. (g) Andrews, P. C.; Peatt, A. C.; Raston, C. L. Tetrahedron
Lett. 2004, 45, 243. (h) Sugiura, M.; Robvieux, F.; Kobayashi, S. Synlett.
2003, 1749.
(8) (a) RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994,
116, 986 and references therein. (b) Gansauer, A.; Pierobon, M.; Bluhm,
H. Synthesis 2001, 2500 and references therein. (c) Justicia, J.; Oller-
Lopez, J. L.; Campana, A. G.; Oltra, J. E.; Cuerva, J. M.; Bunuel, E.;
Cardenas, D. J. J. Am. Chem. Soc. 2005, 127, 14911. (d) Estevez, R. E.;
Lopez, J. L. O.; Robles, R.; Melgarejo, C. R.; Gansauer, A.; Cuerva, J. M.;
Oltra, J. E. Org. Lett. 2006, 8, 5433. (e) Rodriguez, M. M.; Farnandez,
R. G.; Escribano, A. M.; Bermezo, F. A. J. Org. Chem. 2009, 74,
1798. (f) Rasales, A.; Oller-Lopez, J. L.; Justicia, J.; Gansauer, A.;
Oltra, J. E.; Cuerva, J. M. Chem. Commun. 2004, 2628. (g) Campana,
A. G.; Bazdi, B.; Fuentes, N.; Robles, R.; Cuerva, J. M.; Oltra, J. E.
Preparation of N-[1-(1,4-Dioxa-spiro[4.5]dec-2-yl)-but-3-
enyl]-N-(4-methoxy-phenyl)-acrylamide (15c). To a stirred solu-
tion of the homoallyl amine 15b (320 mg, 1 mmol) and Et3N (0.2 mL, 1.5
mmol) in DCM (2 mL) was added acryloyl chloride (120 mg, 1.3 mmol)
in DCM (2 mL) at 0 °C. The reaction mixture was stirred for 1 h at this
temperature then at room temperature for 3 h. The reaction mixture was
quenched with saturated NaHCO3 solution (10 mL) and extracted with
DCM (3 ꢁ 30 mL). The organic layer was washed with water (3 ꢁ
10 mL) and brine (5 mL) and finally dried over Na2SO4. The solvent was
evaporated, and the crude product was subjected to column chromatog-
raphy to furnish the desired acetylated product 15c (300 mg, 80%) as a
pale yellow liquid. IR (neat): 3076, 2937, 2862, 1732, 1643, 1512, 1410,
1
1251, 1101 cmꢀ1. H NMR (500 Mz, CDCl3): δ 1.35ꢀ1.45 (m, 2H),
1.58ꢀ1.67 (m, 8H), 1.81ꢀ2.25 (m, 2H), 2.81ꢀ2.85 (m, 1H), 3.72ꢀ3.76
(m, 1H), 3.83 (s, 3H), 3.87ꢀ3.97 (m, 1H), 4.10ꢀ4.17 (m, 1H), 5.08ꢀ
5.12 (m, 2H), 5.44ꢀ5.48 (m, 1H), 5.79ꢀ5.87 (m, 2H), 6.29ꢀ6.33 (m,
1H), 6.87ꢀ6.89 (m, 2H), 7.03ꢀ7.05 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 24.0, 24.1, 25.3, 32.8, 33.9, 35.0, 35.3, 36.2, 37.4, 38.7, 55.6,
67.3, 67.4, 75.2, 76.6, 109.9, 110.4, 114.5, 117.1, 117.8, 127.6, 128.1, 129.3,
131.6, 134.7, 135.7, 159.5, 159.5, 167.2, 174.7. HRMS: calcd for
C22H29NO4Na [M + Na]+ 394.1994; found 394.1993.
Preparatoin of 6-(1,4-Dioxa-spiro[4.5]dec-2-yl)-1-(4-meth-
oxy-phenyl)-5,6-dihydro-1H-pyridin-2-one (15d). The second
generation Grubbs’ catalyst (75 mg, 10 mol %) was added to a solution of
15c (300 mg, 0.80 mmol) in CH2Cl2 (20 mL) under an argon atmo-
sphere. After being stirred under reflux for 5 h, the resulting solution was
exposed to air with stirring for 1 h, concentrated, and purified by flash
column chromatography on silica gel to give cyclic amide 15d (160 mg,
65%) as a pale yellow liquid. IR (neat): 2935, 2862, 1668, 1510, 1413,
1
1246, 1103 cmꢀ1. H NMR (500 Mz, CDCl3): 1.35ꢀ1.37 (m, 2H),
1.47ꢀ1.56 (m, 8H), 2.78ꢀ2.89 (m, 2H), 3.28 (dd, J = 6.5, 8.5 Hz, 1H),
3.81 (s, 3H), 3.82ꢀ3.90 (m, 2H), 4.24ꢀ4.28 (m, 1H), 6.07 (dd, J = 2.0,
10.0 Hz, 1H), 6.58ꢀ6.92 (m, 1H), 6.89ꢀ6.92 (m, 2H), 7.18ꢀ7.21 (m,
2H). 13C NMR (125 MHz, CDCl3): δ 23.9, 24.1, 25.2, 26.3, 35.0, 36.5,
55.6, 62.0, 67.6, 74.5, 109.7, 114.6, 125.6, 128.6, 134.6, 138.6, 158.3, 163.6.
HRMS: calcd for C20H25NO4Na [M + Na]+ 366.1681; found 366.1618.
’ ASSOCIATED CONTENT
1
S
Supporting Information. Copies of H NMR spectra
b
of 2bꢀ10b, 11bꢀ17b, 17c, 17e, 15c, and 15d and 13C
NMR spectra of 2bꢀ10b, 11bꢀ17b, 17c, 17e, 15c, and 15d.
7233
dx.doi.org/10.1021/jo200908b |J. Org. Chem. 2011, 76, 7229–7234

The Journal of Organic Chemistry
NOTE
Angew. Chem. Int. Ed. 2008, 47, 7515. (h) Sancho-Sanz, I.; Miguel,
D.; Millan, A.; Estevez, R. E.; Oller-Lopez, J. L.; Alvarez-Manzaneda,
E.; Robles, R.; Cuerva, J. M.; Justicia, J. J. Org. Chem. 2011, 76, 732.
(i) Millan, A; Alvarez de Cienfuegos, L.; Martin-Lasanta, A.; Campana, A.
G.; Cuerva, J. M. Adv. Synth. Catal. 2011, 353, 73.(j) Millan, A.; Campana,
A. G.; Bazdi, B.; Miguel, D.; Alvarez de Cienfuegos, L.; Echavarren, A. M.;
Cuerva, J. M. Chem. Eur. J. 2011,17,3985 and references therein.
(9) (a) Roy, S. C.; Rana, K. K.; Guin, C. J. Org. Chem. 2002, 67, 3242.
(b) Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2004, 45, 6575.
(c) Jana, S.; Guin, C.; Roy, S. C. Tetrahedron Lett. 2005, 46, 1155.
(d) Mandal, S. K.; Jana, S.; Roy, S. C. Tetrahedron Lett. 2005, 46, 6115.
(10) Saggiormo, V.; Luning, U. Tetrahedron Lett. 2009, 50, 4663.
(11) Chattopadhyay, S. K.; Biswas, T.; Biswas, T. Tetrahedron Lett.
2008, 49, 1365.
(12) (a) Sharma, G. V. M.; Pendem, N.; Reddy, K. R.; Krishna,
P. R.; Narsimulu, K.; Kunwar, A. C. Tetrahedron Lett. 2004, 45, 8807.
(b) Sundaraju, B.; Sridhar, T.; Achard, M.; Sharma, G. V. M. Eur. J. Org.
Chem. 2010, 6092.
(13) Lam, H. W.; Murry, G. J.; Firth, J. D. Org. Lett. 2005, 7, 5743.
(14) (a) Ma, S.; Ni, B. Org. Lett. 2002, 4, 639. (b) Dhavale, D. D.;
Jachak, S. M.; Karche, N. P.; Trombini, Claudio. Tetrahedron 2004,
60, 3009.
(15) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G. J. Org.
Chem. 1992, 57, 4155.
(16) (a) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 60, 398. (b) Nomura, H; Richards, C. J. Org. Lett. 2009,
11, 2892.
7234
dx.doi.org/10.1021/jo200908b |J. Org. Chem. 2011, 76, 7229–7234