InBr3-catalyzed glycosidation of glycals with arylamines: An alternative approach to access 4-aminocyclopent-2-enones

Article abstract of DOI:10.1021/jo200243d

To turn side products into major products, a novel strategy to access biologically active 4-aminocyclopent-2-enones was developed. These compounds were originally identified as side products but became major products when 3,5-dimethylpyran-3,4-diol 7a was

Full text of DOI:10.1021/jo200243d

ARTICLE
pubs.acs.org/joc
InBr3-Catalyzed Glycosidation of Glycals with Arylamines: An
Alternative Approach To Access 4-Aminocyclopent-2-enones
Fulong Li,†,‡ Chunyong Ding,†,‡ Meining Wang,‡ Qizheng Yao,*,† and Ao Zhang*,‡
†Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
‡Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Shanghai 201203,
China
S Supporting Information
b
ABSTRACT: To turn side products into major products, a
novel strategy to access biologically active 4-aminocyclopent-2-
enones was developed. These compounds were originally
identified as side products but became major products when
3,5-dimethylpyran-3,4-diol 7a was used as the substrate and
30% InBr3 as the catalyst. Aryl- or heteroarylamines as well as variously substituted glycals can be used in this reaction, and the
corresponding 4-aminocyclopent-2-enones were obtained in moderate to good yields. These compounds can be further used to
prepare 4-aminocarbocyclic nucleosides.
’ INTRODUCTION
gram scales. Although the yield of this product was extremely
poor (<5%), we managed to collect sufficient sample and fully
characterize its structure as 5Aa by all spectroscopic data includ-
ing 2D NMR (HMBC, Scheme 1).
Similar side product 5Bb was also obtained in 4% yield after a
close re-examination of the reaction14 between aniline 1B and
glycal 2b confirming the generality of such products in this
reaction. Since compounds 5Aa and 5Bb belong to the 4-ami-
nocyclopent-2-enone class, structurally distinct from our
reported14 glycosidation products 3Aa, 3Bb and 4Aa, 4Bb, this
indicated that a novel synthetic pathway for 4-aminocyclopent-2-
enones might be developed. However, the paucity of the reaction
yields (<5%) and substrate scope need to be fully addressed
before this reaction can be experimentally useful.
In the synthesis of compounds 3Aa, 3Bb and 4Aa, 4Bb, we
have elucidated14 the importance of the 3-OAc group in glycal 2a
or 2b via coordination to InBr3. Therefore, we envisioned that
replacing such fast-moving acetate function in 2a or 2b with a free
hydroxyl group (7b) would possibly slow down or even suppress
the formation of products 3Aa, 3Bb and 4Aa, 4Bb and increase the
formation of 4-aminocyclopent-2-enone 5Aa, 5Bb. In this regard,
using p-chlorobenzenamine 6a as the model substrate, glycosidation
with pyran-3,4-diol 7b was conducted with 10% InBr3 as the catalyst
in CH2Cl2 at rt, a condition14 similar to that of preparation of
compounds 3Aa, 3Bb and 4Aa, 4Bb (Scheme 2).
Unfortunately, this reaction led to a complex mixture contain-
ing several inseparable products. To further prevent the nucleo-
philic attack of aniline to the C-3 of glycal 7b, sterically encumbered
glycal 7a16 bearing a C3-methyl group was employed, and we were
pleased to find that the expected 4-aminocyclopent-2-enone 8aa
The cyclopentanone nucleus is the typical structural core of
natural or synthetic prostaglandins possessing potent antiviral
activity.1ꢀ7 The 2,3-unsaturated versions, cyclopent-2-enones,
especially those with a 4-amino substituent (A, Figure 1) have
also been reported with activity against a wide variety of DNA
and RNA viruses. In early 1987, Masayoshi et al.8 patented a
series of 4-aminocyclopent-2-enones, and similar compounds
with more diversity were further claimed later by Santoro and his
colleagues.5,9,10 In general, these 4-aminocyclopent-2-enones not
only displayed antiviral activity on their own6,7 but also served as
key intermediates to the synthesis of 4-amino carbocyclic nucleo-
sides (B, Figure 1) as analogues of the antiviral drug Carbovir.11
In spite of the interesting biological capacity of 4-aminocy-
clopent-2-enones, synthetic methods to approach this class of
compounds have been less documented. In 1980, Scettri and
colleagues12 reported the first synthesis of 4-aminocyclopent-2-
enones through a two-step process (Michael addition and aldol
condensation). Later, two additional strategies were claimed5,10,12
including direct amination of 4-hydroxycyclopent-2-enone inter-
mediates or Mo-catalyzed ring-opening of DielsꢀAlder cycload-
ducts followed by oxidation. These methods generally suffered
from poor yields or substrate scope limitation.5,8 Therefore, new
methods are needed to readily synthesize this class of compounds
and to assist further evaluation of their pharmaceutical utility.13
’ RESULTS AND DISCUSSION
During our natural product-based drug discovery program,
we14,15 recently found that glycosidation of aniline 1A with glycal
2a yielded two diastereomers 3Aa and 4Aa as the major products
in 56% and 28% yields, respectively (Scheme 1). Interestingly, a
side product was obtained when this reaction was conducted in
Received: February 1, 2011
Published: March 09, 2011
r
2011 American Chemical Society
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was obtained in 48% isolated yield and no cyclization products
structurally similar to 3Aa, 3Bb or 4Aa, 4Bb were isolated at all.
Compound 8aa was also fully characterized by the spectroscopic
7a at all (not shown in the Table 2). It is of note that secondary
amines 6l and 6n also participated in this reaction and offered
products 8la and 8na in 85% and 68% yields, respectively.
However, heteroaryl amine 6m reacted with 7a more slowly,
yielding 4-aminocyclopent-2-enone 8ma in only 33% yield.
It has to be noted that in several cases further glycosidation of
the second NH in anilines with glycal 7a was observed as a
negligible side reaction. However, such side reactions can be
significantly enhanced when 2 equiv or more of glycal 7a was
used, especially in the case of anilines 6o (p-MeO-C6H4NH2), 6p
(p-AcNH-C6H4NH2), and 6q (p-morpholinoaniline) each bearing
an electron-donating substituent. As illustrated in Figure 2, treating
anilines 6oꢀq with 2 equiv of glycal 7a for 24 h afforded
4-aminocyclopent-2-enones 8oa, 8pa, and 8qa in 49%, 41%, and
1
1
data including 2D NMR (HMBC, Hꢀ H COSY, Scheme 2),
and the trans configuration between the 5-methyl and 4-amino
groups was confirmed by the small couplings constant between
H4 and H5 (JH4ꢀH5 = 2.7 Hz) and the NOE interactions
between H4 and 5-Me (see Supporting Information). This result
indicated that 4-aminocyclopent-2-enone 8aa could be prepared
as the major product when a correct substrate, such as glycal 7a,
was employed. It must be noted that no Cotton effect was
observed in the CD spectra of compounds 5Aa and 8aa,
indicating that they were racemates.
To improve the reaction yield, we screened several Lewis acid
catalysts through the model reaction of arylamine 6a and glycal
7a (see Table 1). It was found that 30 mol % of InBr3 offered the
best result leading to product 8aa in 75% isolated yield. Other
Lewis acids including InCl3, In(OTf)3, and FeCl3 also promoted
this reaction, but the yields were lower. Much poorer yield or
decomposition was observed when TMSOTf or AgOTf was used
as the catalyst.
With the optimized reaction conditions, we then set out to
explore the substrate scope and limitation. First, a series of
diversified arylamines (6bꢀn) bearing different substitution
patterns were employed to react with glycal 7a (Table 2). The
reaction generally proceeded smoothly, affording 4-aminocyclo-
pent-2-enones 8baꢀna in moderate to good yields. The location,
size, and electronic properties of the substituents in arylamines
did not play significant roles in the production of the correspond-
ing products, except for unsubstituted aniline 6e, m-toluidine 6g,
and 4-trifluoromethylbenzenamine 6j giving somewhat lower
yields (45ꢀ57%). Naphthalen-2-amine (6i) gave product 8ia
also in lower yield (57%), indicating that the steric effect in the
substrate played a role in the reaction. This was further confirmed
by the finding that naphthalen-1-amine did not react with glycal
Table 1. Optimization of Reactions Conditions of 6a and 7a
entry
Lewis acid
time (h)
solvent
yielda (%)
1
2
3
4
5
6
7
8
9
InBr3 (10 mol %)
InBr3 (30 mol %)
InBr3 (30 mol %)
InCl3 (30 mol %)
In(OTf)3 (30 mol %)
FeCl3 (1.0 equiv)
AuCl3 (30 mol %)
TMSOTf (1.0 equiv)
AgOTf (30 mol %)
2
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
48
75
75
12
36
50
trace
dec
8
12
12
12
10
12
12
12
a Isolated yield of 8aa.
Scheme 2. Reactions of Arylamine 6a with Glycals 7a,b
Figure 1. Reported strategies to access 4-aminocyclopent-2-enones.
Scheme 1. Glycosidation of Arylamines 1A,B and Glycals 2a,b
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51% yields, respectively, along with the corresponding over-reacted
products 8oa0, 8pa0, and 8qa0 in 22%, 32%, and 18% yields.
To further explore the substrate scope, glycals 7a, 7c, 7d, 7e,
and 7f with variant substituents16 were subjected to the same
reaction. As depicted in Table 3, the corresponding 4-aminocy-
clopent-2-enones were obtained in 49ꢀ78% isolated yields. It is
noteworthy that CH2OH-substituted glycals 7e survived the
reaction very well, leading to cyclopentenone 8ae in 64% yield
(entry 4), which could be used for further transformations.
Although InBr3-catalyzed glycosidations of anilines and gly-
cals have been reported previously by us14,15 and others,16,17 the
distinguished different products in the current study indicated
that a new reaction mechanism may exist that favors the forma-
tion of 4-aminocyclopent-2-enones. Therefore, to rationalize this
process, a tentative reaction pathway was proposed according to
Minehan’s report17b involving the formation of a common cationic
intermediate I (Figure 3). Such indate species (I) can be formed
from glycal 7a through a Ferrier-type rearrangement.14,17b Subse-
quent nucleophilic attack by aniline 6e followed by ring-opening
yielded species III, which was then converted to the racemic trans
product, 4-aminocyclopent-2-enone 8ea, through intermediate
IV18,19 by a 4π conrotatory electrocyclization procedure.
To explore the synthetic utility of this methodology, 4-amino carbo-
cyclic nucleosides were prepared from the 4-aminocyclopent-2-enone
Table 2. Substrate Scope Study: InBr3-Catalyzed Glycosida-
tion of Aryl Amines with Glycal 7aa
Figure 3. Possible reaction pathway.
Table 3. Scope Study: Reactions of Arylamines with Different
Glycalsa
entry
arylamine
product
yieldb (%)
1
2
p-Cl-C6H4NH2 (6a)
m-Cl-C6H4NH2 (6b)
p-Br-C6H4NH2 (6c)
p-F-C6H4NH2 (6d)
8aa
8ba
8ca
8da
8ea
8fa
75
65
70
73
57
78
45
68
57
54
78
85
33
68
3
entry
amine
glycals
product
yieldb (%)
4
5
C6H5NH2 (6e)
1
2
6a
6a
6a
6a
6a
6l
7a (R1 = R2 = Me)
8aa
8ac
8ad
8ae
8af
8la
75
49
68
64
63
85
56
76
78
69
6
p-toluidine (6f)
7c (R1 = Me, R2 = H)
7d (R1 = n-Bu, R2 = Me)
7e (R1 = Me, R2 = OHCH2)
7f (R1 = n-Hex, R2 = Me)
7a (R1 = R2 = Me)
7
m-toluidine (6g)
8ga
8ha
8ia
3
8
m,p-(MeO)2-C6H3NH2 (6h)
naphthalen-2-amine (6i)
p-CF3-C6H4NH2 (6j)
biphenyl-4-amine(6k)
N-methylaniline (6l)
5-methylisoxazol-3-amine (6m)
1,2,3,4-tetrahydroquinoline (6n)
4
9
5
10
11
12
13
14
8ja
6
8ka
8la
7
6l
7c (R1 = Me, R2 = H)
7d (R1 = n-Bu, R2 = Me)
7a (R1 = R2 = Me)
8lc
8
6l
8ld
8ka
8kc
8ma
9
6k
8na
10
6k
7c (R1 = Me, R2 = H)
a The concentration was 0.05 M. b Isolated yield.
a The concentration was 0.05 M. b Isolated yield.
Figure 2. Reaction Products of Arylamines 6oꢀq with Excessive Glycal 7a
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Scheme 3. Synthetic Utility Studya
a Reagents and conditions: (i) CeCl3 7H2O, NaBH4, MeOH, rt, 2 h, 99%, (2:1 trans:cis); (ii) (PhCO)2O, DMAP, Py, CH2Cl2, rt, 6 h, isolation, 99%;
3
(iii) LiOH H2O, MeOH/THF/H2O = 5:3:2, rt, 5 h; (iv) 6-chloropurine, DEAD, PPh3, THF, rt, 1 h; (v) 3-N-benzoylthyminel, DEAD, PPh3, THF, rt,
3
overnight; (vi) NH3 in MeOH, rt, overnight.
8la (Scheme 3). Luche reduction of ketone 8la followed by a cis/
trans separation process yielded trans,trans-10a and trans,cis-10b.
Mitsunobu condensation of 10a and 10b with 6-chloropurine
afforded the corresponding carbocyclic nucleosides 11a and 11b
in 75% and 43% yield, respectively. These two compounds can be
used as precursors to prepare diversified nucleosides B (Figure 1)
through further functionalizing the purine 40-Cl substituent.
Similar condensation of 10a or 10b with N-benzoylthyminel20
proved to be sluggish, yielding the corresponding carbocyclic N-
nucleosides 13a and 13b as the major products in moderate
yields, along with corresponding carbocyclic O-nucleosides 12a
and 12b as the minor products. Debenzoylation of 13a and 13b
provided the corresponding carbocyclic N-nucleosides 14 and 15
in 80% and 85% yield, respectively. The relative trans,trans- and
trans,cis-configurations between H1, H4, and H5 in these com-
pounds were determined by the corresponding small coupling
constants11 in the 1H NMR spectra and by the NOE effects of
intermediates 9a,9b.
’ EXPERIMENTAL SECTION
General Procedure for InBr3-Catalyzed Glycosidation of
Glycals and Aryl Amines. InBr3 (21.2 mg, 0.06 mmol) was placed in
a dried reaction flask, which was heated in vacuo and filled with N2. A
solution of an appropriate glycal (0.20 mmol) and a substituted or
unsubstituted aniline (0.20 mmol) in anhydrous CH2Cl2 (4 mL) was
added under N2. The mixture was stirred at 27 °C under N2 for 12 h.
After completion of the reaction, as indicated by TLC, the reaction
mixture was diluted with water and extracted with CH2Cl2 (2 ꢁ 10 mL).
The combined organic layers were dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by column chromatography on
silica gel to afford corresponding 4-aminocyclopent-2-enones 5Aaꢀ8kc.
4-Amino-5-methylcyclopent-2-enone (5Aa): red solid
(obtained as side product in 5% yield); 1H NMR (300 MHz, CDCl3)
δ 9.98 (d, J = 7.5 Hz, 1H), 8.23 (m, 2H), 7.69 (m, 5H), 7.17 (d, J = 8.1
Hz, 1H), 6.36 (m, 1H), 4.55 (m, 1H), 2.45 (m, 1H), 1.40 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 207.8, 185.4, 183.4, 159.3, 150.5,
135.6, 134.9, 134.6 (2C), 134.1, 133.3, 132.8, 126.8, 126.7, 117.5, 116.6,
113.8, 60.5, 49.1, 14.2; MS (EI-LR) 317 (Mþ); HRMS calcd for
C20H15NO3 (Mþ) 317.1052, found 317.1046.
’ CONCLUSION
4-Amino-5-acetyloxymethylcyclopent-2-enone (5Bb): red
solid (obtained as side product in 4% yield); H NMR (300 MHz,
1
A novel strategy to access biologically active 4-aminocyclo-
pent-2-enones was developed. These compounds were originally
identified as side products and then were turned into major
products by using the appropriately substituted glycal substrate
and 30% InBr3 as the catalyst. A variety of aryl- or heteroaryla-
mines as well as diversified glycals were used in this reaction, and
the corresponding 4-aminocyclopent-2-enones were obtained in
moderate to good yields. The unique features of the products not
only provide potential value for drug development but also
provide the basis for further generation of diversified carbocyclic
nucleosides.
CDCl3) δ 9.86 (d, J = 8.7 Hz, 1H), 9.53 (d, J = 9.3 Hz, 1H), 8.29 (d, J =
8.7 Hz, 1H), 8.08 (d, J = 8.7 Hz, 1H), 7.73 (m, 1H), 7.62 (m, 4H), 7.18
(d, J = 7.8 Hz, 1H), 6.41 (m, 1H), 4.96 (d, J = 7.8 Hz, 1H), 4.54 (m, 2H),
2.72 (m, 1H), 2.55 (s, 3H), 2.01(s, 3H); 13C NMR (100 MHz, CDCl3) δ
203.8, 186.3, 185.9, 170.7, 160.8, 149.5, 138.8, 136.7, 136.5, 135.6 (2C),
134.9, 134.5, 132.1, 128.7, 128.3, 128.2, 127.6, 122.2, 116.9, 116.7, 113.2,
61.6, 55.9, 53.3, 21.5, 20.7; MS (EI-LR) 439 (Mþ); HRMS calcd for
C27H21NO5 (Mþ) 439.1420, found 439.1410.
2,5-Dimethyl-4-(4-chlorophenylamino)cyclopent-2-enone
(8aa): colorless oil, 75% yield; 1H NMR (300 MHz, CDCl3) δ 7.19 (s,
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1H), 7.15 (m, 2H), 6.60 (m, 2H), 4.17 (d, J = 6.0 Hz, 1H), 3.77 (br s,
1H), 2.19 (dq, J = 2.7, 7.5 Hz, 1H), 1.80 (s, 3H), 1.31(d, J = 7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 208.8, 153.8, 145.4, 142.3, 129.3 (2C),
122.8, 114.6 (2C), 60.0, 48.9, 14.8, 10.2; MS (EI-LR) 235 (Mþ); HRMS
calcd for C13H14ClNO (Mþ) 235.0764, found 235.0757.
2,5-Dimethyl-4-(4-(trifluoromethyl)phenylamino)cyclo-
pent-2-enone (8ja): white solid, 54% yield; H NMR (300 MHz,
1
CDCl3) δ 7.43 (d, J = 8.7 Hz, 2H), 7.20 (s, 1H), 6.68 (d, J = 8.1 Hz, 2H),
4.28 (m, 1H), 4.06 (m, 1H), 2.23 (dq, J = 2.4 Hz, J = 7.5 Hz, 1H), 1.83 (s,
3H), 1.34 (d, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.4,
153.2, 149.3, 142.7, 126.8 (2C), 112.5 (2C), 59.5, 49.0, 14.8, 10.2; MS
(EI-LR) 269 (Mþ); HRMS calcd for C14H14F3NO (Mþ) 269.1027,
found 269.1027.
4-(Biphenyl-4-ylamino)-2,5-dimethylcyclopent-2-enone
(8ka): yellow solid, 78% yield; 1H NMR (300 MHz, CDCl3) δ 7.43 (m,
6H), 7.25 (m, 2H), 6.73 (d, J = 8.4 Hz, 2H), 4.25 (br s, 1H), 3.82 (br s,
1H), 2.25 (dq, J = 2.4 Hz, J = 7.5 Hz, 1H), 1.82 (s, 3H), 1.34 (d, J = 7.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.0, 154.2, 146.1, 142.1,
140.8, 131.2, 128.6 (2C), 128.1 (2C), 126.2 (3C), 113.7 (2C), 59.9,
49.0, 14.8, 10.2; MS (EI-LR) 277 (Mþ); HRMS calcd for C19H19NO
(Mþ) 277.1467, found 277.1460.
2,5-Dimethyl-4-(methyl(phenyl)amino)cyclopent-2-en-
one (8la): yellow oil, 85% yield; 1H NMR (300 MHz, CDCl3) δ 7.25
(m, 2H), 7.13 (s, 1H), 6.87 (d, J = 8.1 Hz, 2H), 6.79 (m, 1H), 4.66 (d, J =
2.1 Hz, 1H), 2.69 (s, 3H), 2.35 (dq, J = 2.7 Hz, J = 7.5 Hz, 1H), 1.85 (m,
3H), 1.25 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.7,
155.7, 149.7, 142.9, 129.2 (2C), 117.9, 113.9 (2C), 65.9, 44.5, 32.4, 14.6,
10.2; MS (EI-LR) 215 (Mþ); HRMS calcd for C14H17NO (Mþ)
215.1310, found 215.1309.
2,5-Dimethyl-4-(5-methylisoxazol-3-ylamino)cyclopent-
2-enone (8ma): yellow oil, 33% yield; 1H NMR (300 MHz, CDCl3) δ
7.23 (s, 1H), 5.5 (s, 1H), 4.30 (m, 1H), 3.90 (d, J = 9.0 Hz, 1H), 2.30 (s,
3H), 2.21 (dq, J = 2.7 Hz, J = 7.2 Hz, 1H), 1.80 (s, 3H), 1.31 (d, J = 7.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.8, 169.1, 163.7, 154.0,
142.2, 93.3, 60.1, 49.0, 14.4, 12.4, 10.1; MS (EI-LR) 206 (Mþ); HRMS
calcd for C11H14N2O2 (Mþ) 206.1055, found 206.1061.
2,5-Dimethyl-4-(3-chlorophenylamino)cyclopent-2-en-
one (8ba): colorless oil, 65% yield; H NMR (300 MHz, CDCl3) δ
1
7.21 (s, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.71 (m, 1H), 6.65 (t, J = 1.8 Hz,
1H), 6.54 (dd, J = 2.1, 8.1 Hz, 1H), 4.19 (br s, 1H), 3.80 (br s, 1H), 2.19
(dq, J = 2.4, 7.5 Hz, 1H), 1.82 (s, 3H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 208.7, 153.6, 147.9, 142.4, 135.2, 130.4, 118.1,
113.1, 111.7, 59.7, 48.9, 14.8, 10.2; MS (EI-LR) 235 (Mþ); HRMS calcd
for C13H14ClNO (Mþ) 235.0764, found 235.0761.
4-(4-Bromophenylamino)-2,5-dimethylcyclopent-2-en-
one (8ca): yellow oil, 70% yield; 1H NMR (300 MHz, CDCl3) δ 7.27
(m, 3H), 6.54 (m, 2H), 4.17 (s, 1H), 3.73 (br s, 1H), 2.19 (m, 1H), 1.81
(s, 3H), 1.31 (d, J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.8,
153.7, 145.8, 142.4, 132.2, 131.9, 116.7, 115.1, 109.9, 60.0, 48.9, 14.9,
10.2; MS (EI-LR) 279 (Mþ); HRMS calcd for C13H14BrNO (Mþ)
279.0259, found 279.0252.
4-(4-Fluorophenylamino)-2,5-dimethylcyclopent-2-en-
one (8da): colorless oil, 73% yield; H NMR (300 MHz, CDCl3) δ
1
7.21 (s, 1H), 6.91 (m, 2H), 6.62 (m, 2H), 4.15 (s, 1H), 3.52 (br s, 1H),
2.19 (m, 1H), 1.80 (s, 3H), 1.30 (d, J = 7.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 208.9, 156.2 (d, J = 235.5 Hz), 154.1, 143.0, 142.1,
116.0, 115.8, 114.7, 114.6, 60.7, 48.8, 14.8, 10.2; MS (EI-LR) 219 (Mþ);
HRMS calcd for C13H14FNO (Mþ) 219.1059, found 219.1047.
4-(Phenylamino)-2,5-dimethylcyclopent-2-enone (8ea):
1
yellow oil, 57% yield; H NMR (300 MHz, CDCl3) δ 7.23 (m, 3H),
6.77 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8.1 Hz, 2H), 4.23 (d, J = 2.1 Hz, 1H),
3.68 (br s, 1H), 2.23 (dq, J = 2.4 Hz, J = 7.5 Hz, 1H), 1.81 (s, 3H), 1.31 (d, J
= 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 209.1, 154.3, 146.7, 142.0,
129.4 (2C), 118.3, 113.5 (2C), 60.0, 49.0, 14.8, 10.2; MS (EI-LR) 201
(Mþ); HRMS calcd for C13H15NO (Mþ) 201.1154, found 201.1162.
4-(4-Methylphenylamino)-2,5-dimethylcyclopent-2-en-
one (8fa): colorless oil, 78% yield; 1H NMR (300 MHz, CDCl3) δ 7.23
(s, 1H), 7.02 (d, J = 8.1 Hz, 2H), 6.60 (d, J = 8.4 Hz, 2H), 4.20 (s, 1H),
3.48 (br s, 1H), 2.22 (m, 4H), 1.81 (s, 3H), 1.31 (d, J = 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 209.2, 154.5, 144.4, 141.9, 129.9 (2C),
127.7, 113.8 (2C), 60.4, 49.0, 20.3, 14.8, 10.2; MS (EI-LR) 215 (Mþ);
HRMS calcd for C14H17NO (Mþ) 215.1310, found 215.1319.
2,5-Dimethyl-4-(3-tolylamino)cyclopent-2-enone (8ga):
colorless oil, 45% yield; 1H NMR (300 MHz, CDCl3) δ 7.23 (s, 1H),
7.11 (m, 1H), 6.60 (d, J = 6.9 Hz, 1H), 6.50 (s, 2H), 4.22 (s, 1H), 3.67
(br s, 1H), 2.29 (s, 3H), 2.20 (m, 1H), 1.81 (s, 3H), 1.31 (d, J = 7.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 209.1, 154.4, 146.7, 141.9, 139.2,
129.3, 119.2, 114.3, 110.6, 59.9, 49.0, 21.5, 14.8, 10.1; MS (EI-LR) 215
(Mþ); HRMS calcd for C14H17NO (Mþ) 215.1310, found 215.1314.
4-(3,4-Dimethoxyphenylamino)-2,5-dimethylcyclopent-
2-enone (8ha): yellow oil, 68% yield; 1H NMR (300 MHz, CDCl3) δ
7.23 (m, 1H), 6.76 (dd, J = 1.5 Hz, J = 8.4 Hz, 1H), 6.29 (s, 1H), 6.22 (m,
1H), 4.14 (s, 1H), 3.82 (m, 6H), 3.42 (br s, 1H), 2.19 (m, 1H), 1.80 (s,
3H), 1.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 209.2, 154.5, 150.0,
142.3, 142.0, 141.3, 113.0, 104.7, 99.9, 61.1, 56.5, 55.7, 48.9, 14.9, 10.2;
MS (EI-LR) 261 (Mþ); HRMS calcd for C15H19NO3 (Mþ) 261.1365,
found 261.1357.
4-(3,4-Dihydroquinolin-1(2H)-yl)-2,5-dimethylcyclopent-
2-enone (8na): yellow oil, 68% yield; 1H NMR (300 MHz, CDCl3) δ
7.14 (d, J = 1.5 Hz, 1H), 7.01 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 6.64 (t, J
= 7.2 Hz, 1H), 4.71 (s, 1H), 3.07 (m, 2H), 2.78 (t, J = 6.3 Hz, 2H), 2.45
(m, 1H), 1.88 (m, 5H), 1.33 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 209.0, 156.1, 145.1, 142.8, 129.6, 127.0, 123.3, 116.6, 111.2,
64.0, 44.4, 43.4, 28.1, 22.2, 15.0, 10.3; MS (EI-LR) 241 (Mþ); HRMS
calcd for C16H19NO (Mþ) 241.1467, found 241.1469.
4-(4-Methoxyphenylamino)-2,5-dimethylcyclopent-2-en-
one (8oa): yellow oil, 49% yield; 1H NMR (300 MHz, CDCl3) δ 7.23
(s, 1H), 6.80 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz, 2H), 4.14 (s, 1H),
3.75 (s, 3H), 2.18 (m, 1H), 1.80 (s, 3H), 1.29 (d, J = 7.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 209.2, 154.6, 152.8, 141.9, 140.7, 115.4
(2C), 115.0 (2C), 61.2, 55.7, 48.9, 29.6, 14.8, 10.2; MS (EI-LR) 231
(Mþ); HRMS calcd for C14H17NO2 (Mþ) 231.1259, found 231.1260.
4,40-(4-Methoxyphenylazanediyl)bis(2,5-dimethylcyclo-
1
pent-2-enone) (8oa0): yellow oil, 22% yield; H NMR (300 MHz,
CDCl3) δ 7.23 (s, 1H), 7.20 (s, 1H), 6.88 (dd, J = 1.5 Hz, J = 8.7 Hz,
2H), 6.74 (d, J = 8.7 Hz, 2H), 4.02 (m, 2H), 3.74 (s, 3H), 2.31 (m, 2H),
1.77 (s, 6H), 1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 208.5,
208.4, 156.4, 156.2, 142.4, 142.3, 139.2, 138.9, 126.1, 126.0, 114.0 (2C),
67.3, 66.9, 55.3, 46.1, 46.0, 14.1 (2C), 10.3 (2C); MS (EI-LR) 339
(Mþ); HRMS calcd for C21H25NO3 (Mþ) 339.1834, found 339.1842.
N-(4-(3,5-Dimethyl-4-oxocyclopent-2-enylamino)phenyl)
acetamide (8pa): yellow oil, 41% yield; 1H NMR (300 MHz, CDCl3)
δ 7.29 (d, J = 9.0 Hz, 2H), 7.20 (m, 2H), 6.63 (d, J = 9.0 Hz, 2H), 4.18
(br s, 1H), 2.21 (m, 4H), 1.80 (s, 3H), 1.32 (d, J = 7.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 209.0, 168.1, 154.2, 143.9, 142.1, 129.0,
122.4 (2C), 113.9 (2C), 60.4, 48.9, 24.2, 14.8, 10.2; MS (EI-LR) 258
(Mþ); HRMS calcd for C15H18N2O2 (Mþ) 258.1368, found 258.1367.
N-(4-(Bis(3,5-dimethyl-4-oxocyclopent-2-enyl)amino)ph-
enyl)acetamide (8pa0): yellow oil, 32% yield; 1H NMR (300 MHz,
CDCl3) δ 7.59 (br s, 1H), 7.31 (dd, J = 2.1 Hz, J = 8.7 Hz, 2H), 7.20 (m,
2,5-Dimethyl-4-(naphthalene-2-ylamino)cyclopent-2-en-
one (8ia): yellow oil, 57% yield; 1H NMR (300 MHz, CDCl3) δ 7.65
(m, 3H), 7.39 (m, 1H), 7.31 (s, 1H), 7.24 (m, 1H), 6.91 (m, 2H), 4.37
(br s, 1H), 3.89 (br s, 1H), 2.27 (m, 1H), 1.84 (s, 3H), 1.38 (d, J = 7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 209.1, 154.1, 144.4, 142.2, 134.9,
129.3, 127.8, 127.6, 126.5, 125.9, 122.5, 118.1, 105.6, 59.9, 49.0, 14.9,
10.2; MS (EI-LR) 251 (Mþ); HRMS calcd for C17H17NO (Mþ)
251.1310, found 251.1307.
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2H), 6.83 (dd, J = 2.1 Hz, J = 8.7 Hz, 2H), 4.08 (br s, 2H), 2.39 (m, 2H),
2.11 (s, 3H), 1.83 (m, 6H), 1.22 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 208.2, 208.0, 168.3, 156.7 (2C), 143.2, 143.1, 142.8, 142.6, 121.7,
121.6, 121.0, 120.9, 66.4, 65.5, 46.0, 45.7, 24.2, 14.0, 13.9, 10.3, 10.2; MS
(EI-LR) 366 (Mþ); HRMS calcd for C22H26N2O3 (Mþ) 366.1943,
found 366.1930.
1H), 2.26 (m, 2H), 1.52 (m, 2H), 1.38 (m, 2H), 1.26 (d, J = 7.5 Hz, 3H),
0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 208.5, 154.6,
149.7, 147.5, 129.2 (2C), 117.8, 113.9 (2C), 65.9, 44.8, 32.3, 29.6, 24.4,
22.3, 14.6, 13.7; MS (EI-LR) 257 (Mþ); HRMS calcd for C17H23NO
(Mþ) 257.1780, found 257.1776.
4-(Biphenyl-4-ylamino)-2-methylcyclopent-2-enone (8kc):
yellow oil, 69% yield; 1H NMR (300 MHz,CDCl3) δ 7.52 (m, 2H), 7.46
(d, J = 8.7 Hz, 2H), 7.41 (m, 2H), 7.27 (m, 2H), 6.72 (d, J = 8.7 Hz, 2H),
4.67 (d, J = 3.0 Hz, 1H), 3.84 (br s, 1H), 2.95 (dd, J = 6.0 Hz, J = 18.6 Hz,
1H), 2.30 (dd, J = 2.1 Hz, J = 18.6 Hz, 1H), 1.84 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 206.8, 155.5, 145.9, 143.7, 140.8, 131.4, 128.6 (2C), 128.1
(2C), 126.3 (3C), 113.7 (2C), 51.7, 43.1, 10.0; MS (EI-LR) 263 (Mþ);
HRMS calcd for C18H17NO (Mþ) 263.1310, found 263.1302.
2,5-Dimethyl-4-(4-morpholinophenylamino)cyclopent-
2-enone (8qa): colorless oil, 51% yield; 1H NMR (300 MHz, CDCl3)
δ 7.22 (s, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.66 (d, J = 8.4 Hz, 2H), 4.15 (br
s, 1H), 3.83 (m, 4H), 3.43 (br s, 1H), 3.04 (m, 4H), 2.20 (dq, J = 2.4 Hz, J
= 7.5 Hz, 1H), 1.80 (s, 3H), 1.29 (d, J = 7.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 209.2, 154.6, 144.3, 141.9, 140.9, 118.2 (2C), 115.0
(2C), 67.0 (2C), 60.9, 50.9 (2C), 48.9, 14.8, 10.2; MS (EI-LR) 286
(Mþ); HRMS calcd for C17H22N2O2 (Mþ) 286.1681, found 286.1673.
4,40-(4-Morpholinophenylazanediyl)bis(2,5-dimethylcy-
Preparation of (1,5-trans,4,5-trans)-2,5-Dimethyl-4-(me-
thyl(phenyl)amino)cyclopent-2-enyl benzoate (9a) and
(1,5-cis,4,5-trans)-2,5-Dimethyl-4-(methyl(phenyl)amino)
cyclopent-2-enyl Benzoate (9b). Compound 8la (456 mg, 2.121
1
clopent-2-enone (8qa0): colorless oil, 18% yield; H NMR (300
MHz, CDCl3) δ 7.23 (m, 2H), 6.87 (m, 2H), 6.75 (d, J = 8.7 Hz, 2H),
4.03 (s, 2H), 3.84 (s, 4H), 3.08 (s, 4H), 2.34 (m, 2H), 1.78 (s, 6H), 1.25
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 208.4 (2C), 156.6, 156.4,
142.5, 142.3, 125.3, 125.2, 116.2 (2C), 67.3 (2C), 66.8 (2C), 49.5 (2C),
46.2, 46.1, 14.1 (2C), 10.3 (2C); MS (EI-LR) 394 (Mþ); HRMS calcd
for C24H30N2O3 (Mþ) 394.2256, found 394.2253.
mmol) and CeCl3 7H2O (1.58 g, 4.242 mmol) were dissolved in
3
MeOH (50 mL). To the solution was added NaBH4 (160 mg, 4.242
mmol) portionwise. The reaction mixture was stirred at rt for 2 h. After
being quenched with water (1 mL), the solution was concentrated in
vacuo and extracted with CH2Cl2. After being dried over Na2SO4, the
crude product was purified by silica gel chromatography to give the
alcohol intermediate as a mixture of diastereomers (455 mg, 99%) as a
yellow oil. To the above-prepared intermediate (455 mg, 2.097 mmol)
in CH2Cl2 (20 mL) were added pyridine (497 mg, 13.192 mmol),
4-dimethylaminopyridine (25.6 mg, 0.209 mmol), and benzoic anhy-
dride (947 mg, 4.194 mmol), and the reaction was stirred at rt for 6 h.
The mixture was concentrated in vacuo and purified by silica gel
chromatography (EtOAc/hexane 1:80) to give benzoate 9a (443 mg,
1.378 mmol) and benzoate 9b (222 mg, 0.691 mmol).
4-(4-Chlorophenylamino)-2-methylcyclopent-2-enone
(8ac): yellow oil, 49% yield; H NMR (300 MHz, CDCl3) δ 7.25 (s,
1
1H), 7.15 (m, 2H), 6.57 (m, 2H), 4.58 (br s, 1H), 3.76 (br s, 1H), 2.89
(dd, J = 6 Hz, J = 18.6 Hz, 1H), 2.17 (dd, J = 2.1 Hz, J = 18.6 Hz, 1H),
1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.6, 155.1, 145.1, 143.9,
129.3 (2C), 123.1, 114.5 (2C), 51.7, 42.9, 10.0; MS (EI-LR) 221 (Mþ);
HRMS calcd for C12H12ClNO (Mþ) 221.0607, found 221.0608.
2-Butyl-4-(4-chlorophenylamino)-5-methylcyclopent-2-
enone (8ad): yellow oil, 68% yield; 1H NMR (300 MHz, CDCl3) δ
7.15 (m, 3H), 6.59 (d, J = 8.7 Hz, 2H), 4.17 (s, 1H), 3.75 (m, 1H), 2.19
(m, 3H), 1.47 (m, 2H), 1.29 (m, 5H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 208.5, 152.7, 146.8, 145.3, 129.2 (2C), 122.8,
114.5 (2C), 60.1, 49.2, 29.5, 24.4, 22.4, 14.7, 13.7; MS (EI-LR) 277
(Mþ); HRMS calcd for C16H20ClNO (Mþ) 277.1233, found 277.1235.
4-(4-Chlorophenylamino)-5-(hydroxymethyl)-2-methyl-
(1,5-trans,4,5-trans)-2,5-Dimethyl-4-(methyl(phenyl)ami-
no)cyclopent-2-enyl benzoate (9a): 1H NMR (400 MHz,
CDCl3) δ 8.05 (dd, J = 1.2 Hz, J = 8 Hz, 2H), 7.55 (dt, J = 1.2, 7.6
Hz, 1H), 7.44 (dt, J = 1.6, 7.0 Hz, 2H), 7.23 (dt, J = 1.2, 6.8 Hz, 2H), 6.86
(d, J = 8 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H), 5.63 (s, 1H), 5.46 (dd, J = 0.4,
4.0 Hz, 1H), 4.51 (t, J = 1.6 Hz, 1H), 2.79 (s, 3H), 2.25 (m, 1H), 1.82 (s,
3H), 1.31 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4,
150.1, 140.7, 132.9, 131.0, 130.3, 129.5 (2C), 129.1 (2C), 128.4 (2C),
116.9, 113.5 (2C), 86.0, 69.6, 44.6, 32.1, 18.1, 14.1; MS (EI-LR) 321
(Mþ); HRMS calcd for C21H23NO2 (Mþ) 321.1729, found 321.1731.
(1,5-cis,4,5-trans)-2,5-Dimethyl-4-(methyl(phenyl)amino)
cyclopent-2-enyl benzoate (9b): 1H NMR (400 MHz, CDCl3) δ
8.05 (m, 2H), 7.55 (dt, J = 1.2, 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.21
(m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.72 (t, J = 7.2 Hz, 1H), 5.95 (d, J = 6.4
Hz, 1H), 5.71 (s, 1H), 4.82 (m, 1H), 2.73 (s, 3H), 2.47 (m, 1H), 1.82 (s,
3H), 1.08 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.7,
150.4, 140.8, 133.1, 132.9, 130.2, 129.6 (2C), 129.1 (2C), 128.3 (2C),
116.8, 113.5 (2C), 81.8, 70.9, 40.5, 32.0, 14.7, 13.4; MS (EI-LR) 321
(Mþ); HRMS calcd for C21H23NO2 (Mþ) 321.1729, found 321.1731.
Preparation of (1,5-trans,4,5-trans)-2,5-Dimethyl-4-(met-
hyl(phenyl)amino)cyclopent-2-enol (10a) and (1,5-cis,4,5-
trans)-2,5-Dimethyl-4-(methyl(phenyl)amino)cyclopent-2-
1
cyclopent-2-enone (8ae): yellow oil, 64% yield; H NMR (300
MHz, CDCl3) δ 7.30 (s, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.7
Hz, 2H), 4.58 (s, 1H), 4.08 (dd, J = 4.2 Hz, J = 11.1 Hz, 1H), 3.90 (dd, J =
4.8 Hz, J = 11.1 Hz, 1H), 3.80 (br s, 1H), 2.41 (br s, 1H), 2.35 (m, 1H),
1.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.6, 156.1, 145.1, 142.9,
129.3 (2C), 123.1, 114.7 (2C), 60.5, 56.0, 54.6, 10.0; MS (EI-LR) 251
(Mþ); HRMS calcd for C13H14ClNO2 (Mþ) 251.0713, found
251.0713.
4-(4-Chlorophenylamino)-2-hexyl-5-methylcyclopent-2-
enone (8af): yellow oil, 63 yield; 1H NMR (300 MHz, CDCl3) δ 7.14
(m, 3H), 6.59 (d, J = 8.4 Hz, 2H), 4.17 (s, 1H), 3.75 (br s, 1H), 2.18 (m,
3H), 1.45 (m, 2H), 1.28 (m, 9H), 0.87 (t, J = 6.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 208.5, 152.6, 146.9, 145.3, 129.2 (2C), 122.8,
114.5 (2C), 60.1, 49.2, 31.4, 29.0, 27.3, 24.7, 22.4, 14.7, 14.0; MS (EI-
LR) 305 (Mþ); HRMS calcd for C18H24ClNO (Mþ) 305.1546, found
305.1547.
2-Methyl-4-(methyl(phenyl)amino)cyclopent-2-enone
(8lc): yellow oil, 56% yield; 1H NMR (300 MHz, CDCl3) δ 7.25 (m,
3H), 6.84 (m, 3H), 5.04 (br s, 1H), 2.73 (m, 4H), 2.26 (dd, J = 2.1 Hz, J =
18.6 Hz, 1H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 206.9,
157.2, 149.6, 144.0, 129.3 (2C), 118.1, 114.0 (2C), 57.3, 388.2, 32.2,
10.0; MS (EI-LR) 201 (Mþ); HRMS calcd for C13H15NO (Mþ)
201.1154, found 201.1161.
enol (10b). Compound 9a (443 mg, 1.380 mmol) and LiOH H2O
3
(86.8 mg, 2.07 mmol) in MeOH/THF/H2O (5:2:1) (10 mL) were
stirred at rt for 5 h. After evaporation of the solvents, the crude product
was purified by silica gel chromatography to give 10a (239 mg, 80%): 1H
NMR (600 MHz, CDCl3) δ 7.23 (t, J = 7.2 Hz, 2H), 6.86 (d, J = 8.4 Hz,
2H), 6.70 (t, J = 7.2 Hz, 1H), 5.45 (s, 1H), 4.38 (d, J = 1.8 Hz, 1H), 4.02
(d, J = 5.4 Hz, 1H), 2.74 (s, 3H), 1.95 (m, 1H), 1.81 (s, 3H), 1.21 (d, J =
6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.3, 143.6, 129.0 (2C),
128.5, 116.7, 113.4 (2C), 83.8, 68.4, 47.7, 32.1, 17.2, 13.6; MS (EI-
LR) 217 (Mþ); HRMS calcd for C14H19NO (Mþ) 217.1467, found
217.1469.
2-Butyl-5-methyl-4-(methyl(phenyl)amino)cyclopent-2-
enone (8ld): yellow oil, 76% yield; H NMR (300 MHz, CDCl3) δ
1
7.27 (t, J = 7.8 Hz, 2H), 7.11 (s, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.79 (t, J =
6.9 Hz, 1H), 4.68 (s, 1H), 2.71 (s, 3H), 2.38 (dq, J = 2.7 Hz, J = 7.5 Hz,
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Compound 10b (121 mg, 81%) was obtained following the same
procedure as described above: 1H NMR (600 MHz, CDCl3) δ 7.22 (t, J
= 7.8 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.70 (t, J = 7.2 Hz, 1H), 5.55 (s,
1H), 4.72 (m, 1H), 4.43 (d, J = 6.6 Hz, 1H), 2.68 (s, 3H), 2.21 (m, 1H),
1.86 (s, 3H), 1.13 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
150.4, 143.9, 130.8, 129.0 (2C), 116.5, 113.2 (2C), 79.5, 70.0, 41.5, 31.8,
14.5, 12.7; MS (EI-LR) 217 (Mþ); HRMS calcd for C14H19NO (Mþ)
217.1467, found 217.1469.
General Procedure for the Mitsunobu Reaction to Prepare
Compounds 11a, 11b, 12a, 12b, 13a, and 13b. To a suspension
of 10a or 10b (54 mg, 0.249 mmol), PPh3 (163 mg, 0.622 mmol), and
6-chloropurine or 3-N-benzoylthyminel20 (0.298 mmol) in dry THF
(5 mL) at 0 °C was added dropwise a solution of DEAD (40% toluene
solution, 0.27 mL, 0.622 mmol) in dry THF (2 mL). The mixture was
stirred at rt for 1 h, diluted with water, and extracted with CH2Cl2 (2 ꢁ
10 mL). The combined organic layers were dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by column chromatogra-
phy on silica gel (EtOAc/hexane 1:5) to afford the corresponding
condensation product.
4-Amino carbocyclic-N-nucleoside 13b: yellow oil, 44% yield;
1H NMR (300 MHz, CDCl3) δ 7.91 (m, 2H), 7.65 (t, J = 7.4 Hz, 1H),
7.49 (t, J = 8.1 Hz, 2H), 7.26 (m, 2H), 6.91 (m, 3H), 6.80 (t, J = 7.2 Hz,
1H), 5.84 (s, 1H), 5.13 (s, 1H), 4.51 (s, 1H), 2.85 (s, 3H), 2.16 (m, 1H),
1.98 (s, 3H), 1.72 (s, 3H), 1.26 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.9, 162.5, 150.5, 149.8, 138.0, 136.1, 134.9, 133.9, 131.5,
130.3 (2C), 129.1 (4C), 118.1, 114.7 (2C), 111.6, 69.7, 67.6, 45.6, 33.4,
17.5, 14.1, 12.7; MS (EI-LR) 429 (Mþ); HRMS calcd for C26H27N3O3
(Mþ) 429.2052, found 429.2043.
Preparation of 4-Amino Carbocyclic-N-nucleosides 14
and 15. A mixture of 13a or 13b (36 mg, 0.087 mmol) and NH3
(solution in methanol, 1.5 mL) was stirred at rt overnight. The solvent
was evaporated in vacuo, and the crude was purified by column
chromatography (EtOAc/hexane 2:3) to afford 14 or 15 as white solids.
4-Amino carbocyclic nucleoside 14: 80% yield; 1H NMR (300
MHz, CDCl3) δ 9.55 (s, 1H), 7.23 (t, J = 7.5 Hz, 2H), 6.83 (d, J = 8.1 Hz,
2H), 6.74 (m, 2H), 5.90 (s, 1H), 5.55 (d, J = 7.8 Hz, 1H), 4.69 (s, 1H),
2.74 (s, 3H), 2.61 (m, 1H), 1.96 (s, 3H), 1.73 (s, 3H), 0.93 (d, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 163.9, 152.0, 150.1, 138.8, 136.3,
135.8, 129.1 (2C), 117.4, 113.8 (2C), 110.6, 71.8, 65.2, 39.6, 32.1, 14.7,
13.5, 12.7; MS (EI-LR) 325 (Mþ); HRMS calcd for C19H23N3O2 (Mþ)
325.1790, found 325.1793.
4-Amino carbocyclic nucleoside 11a: yellow oil, 75% yield; 1H
NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 7.97 (s, 1H), 7.21 (t, J = 7.8
Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.72 (m, 1H), 6.01 (s, 1H), 5.61 (br s,
1H), 4.88 (br s, 1H), 2.79 (s, 3H), 2.73 (m, 1H), 1.75 (s, 3H), 0.65 (d, J =
6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.2, 151.9, 151.0, 149.9,
143.7, 137.8, 135.9, 131.7, 129.0, 128.7, 117.3, 113.9, 113.5, 70.9, 64.9,
41.0, 32.1, 14.6, 13.0; MS (EI-LR) 353 (Mþ); HRMS calcd for
C19H20ClN5 (Mþ) 353.1407, found 353.1406.
4-Amino carbocyclic nucleoside 15: 85% yield; 1H NMR (300
MHz, CDCl3) δ 9.39 (s, 1H), 7.25 (m, 2H), 6.89 (d, J = 8.1 Hz, 2H),
6.83 (s, 1H), 6.78 (t, J = 7.2 Hz, 1H), 5.79 (s, 1H), 5.14 (s, 1H), 4.52 (m,
1H), 2.83 (s, 3H), 2.11 (s, 1H), 1.94 (d, J = 0.9 Hz, 3H), 1.66 (s, 3H),
1.25 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.8, 151.6,
149.8, 138.3, 136.3, 133.3, 129.1, 117.9, 114.6, 111.6, 69.6, 67.3, 45.5,
33.2, 17.3, 14.0, 12.6; MS (EI-LR) 325 (Mþ); HRMS calcd for
C19H23N3O2 (Mþ) 325.1790, found 325.1787.
4-Amino carbocyclic nucleoside 11b: yellow oil, 43% yield; 1H
NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.06 (s, 1H), 7.24 (m, 2H),
6.88 (d, J = 8.7 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1H), 5.86 (d, J = 1.2 Hz, 1H),
5.06 (d, J = 7.5 Hz, 1H), 4.65 (m, 1H), 2.90 (s, 3H), 2.55 (m, 1H), 1.60
(s, 3H), 1.26 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9,
151.8, 151.1, 149.8, 144.0, 137.6, 132.8, 131.8, 129.1 (2C), 117.7, 114.1
(2C), 69.6, 68.6, 46.3, 32.9, 17.4, 13.9; MS (EI-LR) 353 (Mþ); HRMS
calcd for C19H20ClN5 (Mþ) 353.1407, found 353.1408.
4-Amino carbocyclic-O-nucleoside 12a: yellow oil, 8% yield;
1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 8.19 (d, J = 7.2 Hz, 2H),
7.67 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.23 (t, J = 7.8 Hz, 2H),
6.82 (d, J = 8.1 Hz, 2H), 6.69 (t, J = 7.2 Hz, 1H), 5.98 (d, J = 6.9 Hz, 1H),
5.66 (s, 1H), 4.82 (s, 1H), 2.71 (s, 3H), 2.49 (m, 1H), 2.15 (s, 3H), 1.84
(s, 3H), 1.05 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.2,
164.6, 163.1, 161.7, 150.4, 141.0, 134.2, 132.5, 130.4 (2C), 129.0 (2C),
128.7 (2C), 128.3, 116.6, 115.4, 113.3 (2C), 84.5, 70.5, 40.8, 32.0, 14.8,
13.4, 12.1; MS (EI-LR) 429 (Mþ); HRMS calcd for C26H27N3O3 (Mþ)
429.2052, found 429.2049.
’ ASSOCIATED CONTENT
S
Supporting Information. General information and co-
b
pies of 1H and 13C NMR spectra for the characterization of all
final compounds are reported. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: qz_yao@yahoo.com.cn; aozhang@mail.shcnc.ac.cn.
’ ACKNOWLEDGMENT
The authors are grateful to the Chinese National Science
Foundation (81072528), Shanghai Commission of Science and
Technology (10410702600, 10JC1417100, 10dz1910104), and
National Science & Technology Major Project on “Key New
Drug Creation and Manufacturing Program” (2009ZX09301-
001, 2009ZX09103-062). A grant from the Key Laboratory of
Pesticide & Chemical Biology, Central China Normal University
(201005A02), is also appreciated.
4-Amino carbocyclic-N-nucleoside 13a: yellow oil, 20% yield;
1H NMR (300 MHz, CDCl3) δ 7.90 (m, 2H), 7.64 (t, J = 7.5 Hz, 1H),
7.49 (t, J = 7.5 Hz, 2H), 7.25 (t, J = 8.1 Hz, 2H), 6.85 (m, 3H), 6.77 (t, J =
7.5 Hz, 1H), 5.96 (s, 1H), 5.52 (d, J = 8.1 Hz, 1H), 4.73 (m, 1H), 2.74 (s,
3H), 2.61 (m, 1H), 2.00 (s, 3H), 1.79 (s, 3H), 1.02 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 168.9, 162.6, 150.8, 150.1, 138.3, 136.5,
136.0, 134.9, 131.5, 130.2 (2C), 129.2 (2C), 129.1 (2C), 117.5, 113.8
(2C), 110.7, 71.7, 65.6, 39.7, 32.1, 14.9, 13.6, 12.8; MS (EI-LR) 429
(Mþ); HRMS calcd for C26H27N3O3 (Mþ) 429.2052, found 429.2044.
4-Amino carbocyclic-O-nucleoside 12b: yellow oil, 25% yield;
1H NMR (300 MHz, CDCl3) δ 8.41 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H),
7.68 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H),
6.84 (d, J = 8.5 Hz, 2H), 6.69 (t, J = 7.2 Hz, 1H), 5.58 (s, 1H), 5.47 (d, J =
3.6 Hz, 1H), 4.49 (s, 1H), 2.76 (s, 3H), 2.28 (m, 1H), 2.16 (s, 3H), 1.83
(s, 3H), 1.30 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.1,
164.4, 163.1, 161.7, 150.2, 141.1, 134.2, 130.5, 130.4 (2C), 129.0 (2C),
128.7 (2C), 128.3, 116.6, 115.5, 113.3 (2C), 88.7, 69.4, 44.5, 32.1, 18.3,
14.3, 12.1; MS (EI-LR) 429 (Mþ); HRMS calcd for C26H27N3O3 (Mþ)
429.2052, found 429.2048.
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