First example of a Prins-Ritter reaction on terpenoids: A diastereoselective route to novel 4-amido-octahydro-2H-chromenes

Article abstract of DOI:10.1039/c4ra02124j

(-)-Isopulegol was subjected to a triflic acid-promoted three-component Prins-Ritter reaction with a series of aldehydes to produce a library of novel 4-acetamido-octahydro-2H-chromene derivatives in good yields and high diastereoselectivities. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02124j

RSC Advances
View Article Online
View Journal | View Issue
PAPER
First example of a Prins–Ritter reaction on
terpenoids: a diastereoselective route to novel 4-
Cite this: RSC Adv., 2014, 4, 22387
amido-octahydro-2H-chromenes†
a
a
Barnali Sarmah, Gakul Baishya and Rajani K. Baruahb
*
Received 11th March 2014
Accepted 28th April 2014
(ꢀ)-Isopulegol was subjected to a triflic acid-promoted three-component Prins–Ritter reaction with a
series of aldehydes to produce a library of novel 4-acetamido-octahydro-2H-chromene derivatives in
good yields and high diastereoselectivities.
DOI: 10.1039/c4ra02124j
www.rsc.org/advances
Ritter reaction sequence can be efficiently utilized for the
synthesis of optically pure natural alkaloids (ꢀ)-halosaline
and (ꢀ)-norallosedamine without loss of their optical
Introduction
The highly functionalized tetrahydropyran ring, the key
structural motif of many biologically and synthetically
important natural products, has attracted a great deal of
attention in the eld of synthetic organic chemistry.1 The
construction of tetrahydropyran rings is generally achieved in
a single step chemical process via the well-known Prins
cyclization reaction of homoallylic alcohols with aldehydes or
ketones.2 Recently, one-pot, three-component reactions have
shown their potential in various applications of pharmaceu-
tical chemistry such as the production of structural scaffolds
and in combinatorial libraries for drug discovery.3 The Prins
cyclization method could be utilized as an initiator of a
tandem three-component reaction because the carbocation
formed during the course of the reaction has to be quenched
with various nucleophiles.4 Moreover, the technique of a
tandem reaction is also a valuable synthetic tool that plays an
important role in the synthesis of natural product-like mole-
cules.5 The major advantage of a tandem reaction is the
consecutive formation of several covalent bonds, including C–
C, C–O, and C–N, among others, by a single catalyst in one-pot.
Again, amino tetrahydropyrans are the core structures of many
natural products such as ambrucitin VS, oligomer of glyca-
mino acids, sialic acid and dysiherbaine, etc.7 Various appli-
cations8 of these compounds in photographic plates as well as
in host–guest chemistry are well documented in the literature.
The sequence of the Prins–Ritter reaction could be utilized as
the best synthetic method to build the six membered ring of 4-
amino tetrahydropyran derivative efficiently in a single step
reaction (Scheme 1).6 It is also well established that the Prins–
purities.6
Perron and Albizati rst developed a tandem Prins–Ritter
sequence wherein 4-acetamido-pyranosides were synthesized
through a SnCl4 mediated reaction of orthoesters with homo-
allylic alcohols in acetonitrile.4e Willis and co-workers also
reported the Prins–Ritter tandem cyclization of acetal of a
homoallylic alcohol in the presence of triic acid in acetoni-
trile.9 Recently, Yadav et al. also demonstrated the tandem
Prins–Ritter reaction of homoallylic alcohols, aldehydes or
ketones and nitriles in two different reports using a catalytic
mixture CeCl3–acetyl chloride10a and phosphomolybdic acid.10b
The Sakurai–Prins–Ritter reaction sequence was also efficiently
employed to synthesize synthetically important 4-acylamino-
2,6-disubstituted tetrahydropyran derivatives.11 Again, 2H-
chromene12 is also found to be the core structural motif of
several biologically active natural products such as calonolide F,
which was isolated from Calophyllum teysmannii.13 Calonolide F
mainly exhibits anti-HIV activity, whereas its synthetic
analogues show anti-hypertensive14 and anti-ischaemic15 activ-
ities. Although there are many existing reports on Prins–Ritter16
and Sakurai–Prins–Ritter reactions in the literature, to the best
of our knowledge, this is the rst example of the synthesis of
aNatural Products Chemistry Division, CSIR-North East Institute of Science
&
Technology, Jorhat-785006, India. E-mail: b.gakul@gmail.com; Fax: +91-376-2370011
bAnalytical Chemistry Division, CSIR-North East Institute of Science & Technology,
Jorhat-785006, India. Fax: +91-376-2370011
† CCDC 968993. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/c4ra02124j
Scheme 1 Prins–Ritter reaction sequence.
RSC Adv., 2014, 4, 22387–22397 | 22387
This journal is © The Royal Society of Chemistry 2014

View Article Online
RSC Advances
Paper
novel 4-acetamido-octahydro-2H-chromene derivatives via the 2.0 equivalent of triic acid. We found that the formation of the
normal Prins cyclized product could not be completely avoided
Prins–Ritter reaction of (ꢀ)-isopulegol with aldehydes.
As a part of our ongoing research programme on the Prins and 8–9% yield of 5c and 6c were also obtained in each case.
cyclization reaction,17 we report herein the successful execution Thus, the optimal reaction conditions involved the use of
of the Prins–Ritter strategy for the synthesis of a library of novel (ꢀ)-isopulegol 1 (1 mmol) with p-anisaldehyde 2c (1.2 mmol)
4-acetamido-octahydro-2H-chromene derivatives from (ꢀ)-iso- and a solution of 2 equivalents of triic acid (2 mmol) as
ꢁ
pulegol and aldehydes using triic acid as a promoter under the promoter in 1 mL CH2Cl2 in acetonitrile (1 mL) at ꢀ25 C
very mild conditions (Scheme 1, This report).
(Table 1).
Aer optimization of the reaction conditions, we explored
the general applicability and scope of this protocol with various
aromatic and aliphatic aldehydes; the results are presented in
the Table 2.
The exploration of this Prins–Ritter protocol began with the
reaction of (ꢀ)-isopulegol with various aromatic and hetero-
aromatic aldehydes. Various substituted aromatic aldehydes
including p-tolualdehyde, p-isopropylbenzaldehyde, m-nitro-
Results and discussions
In search of optimal reaction conditions, we rst attempted the
reaction of (ꢀ)-isopulegol (1 mmol) with p-anisaldehyde
(1.2 mmol) using 1 equivalent of triic acid (1 mmol) as a
promoter in acetonitrile at 24 ꢁC. But the reaction gave a
complex mixture of products. Repeating the reaction at 0 ꢁC as
well as ꢀ10 ꢁC failed to control the formation of by-products. As
such, we considered performing the reaction at a lower
temperature to address the problem of formation of multiple
products. Thus, we performed the same reaction at ꢀ20 ꢁC
using one equivalent of triic acid. This time, the reaction
proceeded smoothly affording a diastereomeric mixture of
Prins–Ritter products 3c and 4c, as conrmed by their 1H NMR
spectra, along with the diastereomeric mixture of the normal
Prins cyclized products, 5c and 6c. However, the yield of the
reaction was very poor (37%). To obtain a better yield, we also
increased the amount of TfOH to 1.5, 2.0 and 3.0 equivalents to
obtain the diastereomeric mixture of Prins–Ritter products in
53%, 72% and 70% yields, respectively. However, 10–13% yield
of the normal Prins cyclized product (5c and 6c) was also iso-
lated in each case. In subsequent experiments, we also tried to
stop the formation of the normal Prins cyclized product by
decreasing the temperature to ꢀ25 ꢁC, ꢀ40 ꢁC and ꢀ50 ꢁC using
benzaldehyde,
p-chlorobenzaldehyde,
3,4-dichlor-
obenzaldehyde and p-bromobenzaldehyde underwent the
Prins–Ritter reaction smoothly to produce their corresponding
4-acetamido-octahydro-2H-chromene derivatives under the
optimized reaction conditions (entries d–i, Table 2). The crude
products were puried by column chromatography to afford
pure 4-acetamido-octahydro-2H-chromenes. However, the 1H
NMR spectra of the pure products aer column chromatog-
raphy revealed the presence of a mixture of two diastereomers.
In order to separate the two diastereomers, we performed a re-
crystallization and successfully separated both species as opti-
cally pure diastereomers. Both aromatic aldehydes bearing
electron donating and electron withdrawing substituents
afforded 4-acetamido-octahydro-2H-chromene derivatives in
good yields; however, the ratios of diastereomers obtained aer
re-crystallization were higher in the case of aromatic aldehydes
with electron donating substituents. Unsubstituted aromatic
Table 1 Reaction condition optimization studies using (ꢀ)-isopulegol 1 and p-anisaldehyde 2ca
Entry
TfOH (equiv.)
Temperature
24 ꢁ
Time
Yieldb (%) 3c + 4c
Yieldb (%) 5c + 6c
1
2
3
4
5
6
7
8
9
10
1.0
1.0
1.0
1.0
1.5
2.0
3.0
2.0
2.0
2.0
C
1 h
1 h
1 h
45 min
45 min
45 min
45 min
45 min
45 min
45 min
—
—
—
37
53
72
70
76
76
74
—
—
—
12
13
10
14
7
0 ꢁ
C
ꢀ10 ꢁC
ꢀ20 ꢁC
ꢀ20 ꢁC
ꢀ20 ꢁC
ꢀ20 ꢁC
ꢀ25 ꢁC
ꢀ40 ꢁC
ꢀ50 ꢁC
8
7
a
Reaction conditions: reaction performed with 1.2 mmol of 2c and 1 mmol of 1 at a1 : 1 ratio of CH3CN/CH2Cl2 in 2 mL solution. b Yields are for
isolated products as mixtures.
22388 | RSC Adv., 2014, 4, 22387–22397
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 2 Scope of the triflic acid promoted Prins–Ritter reaction of (ꢀ)-isopulegol
Entry
Aldehyde R¼
Product 3a
Product 4a
% Yieldb
Ratio 3 : 4c
a
Ph
62
5 : 1
b
2-Naphthyl
4-MeO-Ph
4-Me-Ph
68
76
72
4 : 1
5 : 1
5 : 1
c
d
e
4-iso-Propyl-Ph
76
4 : 1
f
3-NO2-Ph
64
70
3.5 : 1d
g
4-Cl-Ph
5 : 1
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 22387–22397 | 22389

View Article Online
RSC Advances
Paper
Table 2 (Contd.)
Entry
Aldehyde R¼
Product 3a
Product 4a
% Yieldb
Ratio 3 : 4c
h
3,4-Cl2-Ph
60
5 : 1
i
4-Br-Ph
62
4 : 1
j
2-Furfuryl
67
64
3 : 1
k
2-Thiophenyl
3.5 : 1
l
n-Ethyl
60
62
2 : 1
m
3-Phenyethyl
2 : 1
e
n
iso-Propyl
58
—
22390 | RSC Adv., 2014, 4, 22387–22397
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Table 2 (Contd.)
Entry
Aldehyde R¼
Product 3a
Product 4a
% Yieldb
Ratio 3 : 4c
o
Cyclohexyl
65
3 : 1
a
Products 3 and 4 were characterized by their 1H NMR, 13C NMR, mass and IR spectra. b Combined isolated yields. c Diastereomeric ratios were
obtained from their isolated yields. d Diasteromeric ratio was obtained from its 1HNMR spectrum. e Major isomer 3n was exclusively obtained and
4n was not isolated in a trace amount.
aldehydes such as benzaldehyde and 2-napthaldehyde also diastereoselectivity (7 : 8 ¼ 4 : 1) (Scheme 2). Like other
underwent a Prins–Ritter reaction to afford their correspond- aliphatic aldehydes, the diastereomers obtained in this case
ing 4-acetamido-octahydro-4H-chromene in good yields and were also separated by silica gel column chromatography.
good diastereoselectivities (entries a & b, Table 2). Interest-
In subsequent experiments, we also explored the addition
ingly, the Prins–Ritter reaction of heteroaromatic aldehydes of diversity at the 4-position of the chromene derivatives using
including 2-furfuraldehye and 2-thiophene carbaldehyde different nitrile molecules. Thus, different nitrile molecules
with (ꢀ)-isopulegol under the same reaction condition also including benzonitrile, acrylonitrile, piperonitrile were reac-
afforded their corresponding acetamido chromene derivatives ted with (ꢀ)-isopulegol and p-anisaldehyde in three different
in good yields and good diastereoselectivities (entries j & k, reactions. We found that only benzonitrile underwent the
Table 2).
Prins–Ritter sequence to afford the corresponding 4-benza-
To conrm the utility of this protocol, various aliphatic mido-octahydro-2H-chromene derivatives 9 and 10 in good
aldehydes were also reacted with (ꢀ)-isopulegol and acetonitrile yield. In addition, the diastereoselectivity could not be ach-
under the same reaction conditions. For example, propanal, 3- ieved from the isolated yield because isomer 9 could not be
phenyl propanal, cyclohexyl carbaldehyde and iso- isolated in its pure form by normal silica gel column chro-
butaraldehyde also underwent a smooth Prins–Ritter reaction matography (Scheme 3).
with (ꢀ)-isopulegol and acetonitrile in the presence of 2
A possible mechanism for this important transformation has
equivalents of triic acid at ꢀ25 ꢁC to yield their corresponding been proposed in Scheme 4. It has been shown that the alde-
4-acetamido-octahydro-2H-chromenes (entries l–o, Table 2). hyde group is rst protonated by the triic acid that has been
Surprisingly, the products were also obtained in good yields and attacked by the hydroxyl group of the isopulegol molecule. The
good diastereoselectivities using these aldehydes. However, in subsequent proton transfer followed by the removal of a water
the case of aliphatic aldehydes, the diastereomers produced in molecule leads to the oxocarbenium ion A that undergoes a
each reaction were separated by simple silica gel column Prins cyclization via its common cis-selective pathway to
chromatography.
produce the tetrahydropyranyl tertiary carbocation B. The
Furthermore, it has been established that this methodology nucleophile (acetonitrile) present in the reaction medium
can be extended to conjugated aldehydes and works well with attacks the carbocation B from either sides to give the inter-
cinnamaldehyde to furnish the corresponding 4-acetamido- mediates C and D, which under hydrolysis give the desired
octahydro-2H-chromenes 7 and 8 in moderate yield and good products. The major isomer possesses the equatorial acetamide
Scheme 2
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 22387–22397 | 22391

View Article Online
RSC Advances
Paper
Scheme 3 Synthesis of 4-benzamido-octahydro-2H-chromen from (ꢀ)-isopulegol.
Scheme 4 Mechanism of the Prins–Ritter reaction of (ꢀ)-isopulegol.
Experimental
General methods
Melting points were measured using a Buchi B-540 melting
point apparatus and are uncorrected. IR spectra were recorded
on a SHIMADZU FTIR-8400. NMR spectra were recorded on a
Bruker DPX 300 MHz, AV500 Advance-III 500 MHz and Jeol JNM
400 MHz spectrometers using tetramethylsilane (TMS) as an
internal standard. Mass spectra were recorded on an ESQUIRE
3000 Mass spectrometer. All the commercially available
reagents were used without further purication. All experiments
were monitored by thin layer chromatography using aluminum
pre-coated silica gel TLC plates (Merck). Aer elution, the spots
were visualized under UV illumination at 254 nm. Further
visualization was achieved by staining the anisaldehyde char-
ring solution. Column chromatography was performed on silica
gel (100–200 mesh, Rankem) using an appropriate ethyl
Fig. 1 Single X-ray crystallographic structure of the compound 3c.
group, which was conrmed by the single-X-ray crystallography
of 3c (Fig. 1) and NOESY experiment of 4c. These results
indicate that the trapping of the carbocation B favors the
equatorial side.
Conclusion
In conclusion, an operationally simple method has been acetate–hexane mixture. Specic rotation values were measured
developed for the diastereoselective synthesis of novel 4-acet- on a PerkinElmer Polarimeter model 343.
amido-octahydro-2H-chromene derivatives using a one-pot
General procedure for the preparation of compounds 3 and
sequential Prins–Ritter reaction of (ꢀ)-isopulegol with alde- 4. To a solution of (ꢀ)-isopulegol (1.0 mmol), aldehyde 1 (1.2
hydes in the presence of triic acid as the promoter under very mmol) and dry acetonitrile (1 mL), a solution of triic acid (2.0
mild reaction conditions. A wide range of non-substituted and mmol in 1 mL CH2Cl2) was added dropwise and the mixture was
substituted aromatic aldehydes with both electron donating stirred at ꢀ25 ꢁC for 30 min. The reaction mixture was allowed
and electron withdrawing substituents underwent a Prins–Rit- to warm up to 0 ꢁC over 45 min. Aer the completion of the
ter reaction with (ꢀ)-isopulegol. This protocol was also equally reaction as determined by TLC, 10 mL of a saturated aq.
effective with various aliphatic and conjugated aldehydes. The NaHCO3 solution was added to the reaction mixture and
triic acid promoted Prins–Ritter reaction offers a new synthetic extracted with ethyl acetate (3 ꢂ 10 mL). The organic layer was
route for the synthesis of novel 4-amido-octahydro-2H-chro- washed with brine (1 ꢂ 10 mL) and dried over anhydrous
mene derivatives in a single step.
sodium sulphate. The organic layer was concentrated under
22392 | RSC Adv., 2014, 4, 22387–22397
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
rotary evaporator and separated using column chromatography (s, 3H), 3.46 (td, 1H, J ¼ 10.4, 4.2 Hz), 2.36 (dd, J ¼ 13.2, 2.2 Hz,
on silica gel (100–200 mesh) using 3 : 7 ethyl acetate–hexane as 1H), 2.23–1.98 (m, 2H), 1.92 (s, 3H), 1.75–1.71 (m, 3H), 1.46 (s,
the eluent to obtain the Prins–Ritter products 3 and 4 (as dia- 3H), 1.17–0.98 (m, 4H), 0.94 (d, J ¼ 6.4 hz, 3H). 13C NMR (75
stereomeric mixture as conrmed by its 1H NMR spectrum). The MHz, CDCl3): d 169.5, 158.9, 134.5, 127.4, 113.6, 75.9, 75.3, 55.2,
two diastereomers were separated from the mixture by re-crys- 55.1, 47.5, 45.4, 41.6, 34.3, 31.3, 24.6, 23.5, 22.1, 18.9. IR
tallization from hexane. The structure of compounds 5c and 6c (CHCl3): 3310.4, 2948.9, 2926.4, 2858.7, 1654.2, 1514.6 cmꢀ1
.
was conrmed by comparing their analytical data with those ESI (MS): m/z ¼ 354 [M + Na]+, Anal. calcd for C20H29NO3: C
reported in the literature.17a
72.47, H 8.82, N 4.23; found: C 72.42, H 8.76, N 4.19.
N-(4,7-Dimethyl-2-phenyl-octahydro-chromen-4-yl)-acetamide
N-[2-(4-Methoxy-phenyl)-4,7-dimethyl-octahydro-chromen-4-yl]-
(3a). White solid; m.p. 197.4 ꢁC. [a]2D0 ¼ +6.0 (c 0.1). 1H NMR (300 acetamide (4c). Semisolid. [a]2D0 ¼ +38.0 (c 0.3). 1H NMR (300
MHz, CDCl3): d 7.36–7.20 (m, 5H), 5.30 (s, 1H), 4.53 (dd, J ¼ 11.7, MHz, CDCl3) d 7.29 (d, J ¼ 8.6 Hz, 2H), 6.85 (d, J ¼ 8.6 Hz, 2H),
1.8 Hz, 1H), 3.47 (td, J ¼ 10.4, 4.2 Hz, 1H) 2.41 (dd, J ¼ 13.2, 5.29 (s, 1H), 4.51 (d, J ¼ 10.3 Hz, 1H), 3.78 (s, 3H), 3.44 (td, J ¼
2.1 Hz, 1H), 2.21–2.04 (m, 3H), 1.91 (s, 3H), 1.76–1.71 (m, 2H), 10.4, 4.2 Hz 1H), 3.07 (dd, J ¼ 13.8, 1.6 Hz, 1H), 1.96 (s, 3H),
1.47 (s, 3H), 1.19–0.99 (m, 4H), 0.95 (d, J ¼ 6.48 Hz, 3H). 13C 2.02–1.78 (m, 3H), 1.44 (s, 3H), 1.46–1.38 (m, 2H), 1.26–1.01 (m,
NMR (75 MHz, CDCl3): d 169.4, 142.3, 128.2, 127.3, 126.0, 75.9, 3H), 0.94 (d, 3H, J ¼ 6.15 Hz), 0.94–0.92 (m, 1H). 13C NMR (100
75.7, 55.1, 47.7, 45.6, 41.5, 34.3, 31.3, 24.7, 23.5, 22.1, 18.9. IR MHz, CDCl3): d 170.0, 158.7, 134.4, 127.2, 113.6, 75.7, 75.5, 58.2,
(CHCl3): 3306.2, 2925.0, 2857.5, 1650.1, 1551.3 cmꢀ1. ESI (MS): 54.0, 50.6, 42.5, 41.5, 36.6, 34.3, 31.2, 24.6, 23.0, 22.1. IR
m/z ¼ 324 [M + Na]+. Anal. calcd for C19H27NO2: C, 75.71; H, (CHCl3): 3337.0, 2925.6, 2868.5, 1652.1, 1514.0 cmꢀ1. ESI (MS):
9.03; N, 4.65; found: C 75.67, H 9.07, N 4.60.
m/z ¼ 332 [M + 1]+.
N-(4,7-Dimethyl-2-phenyl-octahydro-chromen-4-yl)-acetamide
N-(4,7-Dimethyl-2-p-tolyl-octahydro-chromen-4-yl)-acetamide
1
20
1
(4a). Gummy liquid. [a]2D0 ¼ +30.0 (c 0.3). H NMR (300 MHz, (3d). White solid, m.p. 233.7 C. [a]D ¼ +2.0 (c 0.16). H NMR
CDCl3): d 7.35–7.19 (m, 5H), 5.30 (s, 1H), 4.57 (dd, J ¼ 11.6, 1.6 (300 MHz, CDCl3): d 7.24 (d, J ¼ 8.0 Hz, 2H), 7.11–7.09 (m, J ¼
Hz, 1H), 3.45 (td, J ¼ 10.4, 4.3 Hz, 1H), 3.13 (dd, J ¼ 13.9, 1.8 Hz, 7.9 Hz, 2H), 5.21 (s, 1H), 4.49 (dd, J ¼ 11.7, 1.8 Hz, 1H), 3.46 (td,
1H), 2.03 (s, 3H), 1.97–1.91 (m, 3H), 1.47–1.43 (m, 2H), 1.42 (s, J ¼ 14.3, 4.2 Hz, 1H), 2.38 (dd, J ¼ 13.3, 2.1 Hz, 1H), 2.30 (s, 3H),
3H), 1.00–0.97 (m, 4H), 0.95 (d, J ¼ 6.3 Hz, 3H). 13C NMR (75 2.20–1.99 (m, 3H), 1.91 (s, 3H), 1.75–1.71 (m, 2H), 1.46 (s, 3H),
MHz, CDCl3): d ¼ 169.7, 142.2, 128.2, 127.2, 125.8, 74.8, 53.9, 1.18–0.98 (m, 4H), 0.95 (d, 3H, J ¼ 6.4 Hz). 13C NMR (75 MHz,
50.7, 42.7, 41.5, 34.3, 31.3, 24.8, 24.5, 22.9, 22.1. IR (CHCl3): CDCl3): d ¼ 169.4, 139.3, 136.9, 128.9, 126.0, 75.9, 75.6, 55.1,
3336.8, 2925.9, 2869.2, 1655.3, 1535.5 cmꢀ1. ESI (MS): m/z ¼ 324 47.7, 45.5, 41.6, 34.4, 31.3, 24.7, 23.5, 22.1, 21.1, 18.9. IR
ꢁ
[M + Na]+.
(CHCl3): 3308.5, 2948.4, 2925.1, 2859.5, 1655.1, 1551.1 cmꢀ1
.
N-(4,7-Dimethyl-2-naphthalen-2-yl-octahydro-chromen-4-yl)- ESI (MS): m/z ¼ 338 [M + Na]+. Anal. calcd for C20H29NO2: C
20
ꢁ
acetamide (3b). White solid; m.p. 214.5 C. [a]D ¼ +7.0 (c 0.1). 76.15; H, 9.27; N, 4.44; found: C 76.10, H 9.23, N 4.48.
1H NMR (300 MHz, CDCl3): d 7.82–7.77 (m, 4H), 7.50–7.39 (m,
N-(4,7-Dimethyl-2-p-tolyl-octahydro-chromen-4-yl)-acetamide
3H), 5.35 (s, 1H), 4.70 (dd, J ¼ 11.7, 1.7 Hz, 1H), 3.53 (dt, J ¼ (4d). Gummy liquid. [a]2D0 ¼ +31.0 (c 0.24). H NMR (300 MHz,
14.4, 4.1 Hz, 1H), 2.48 (dd, J ¼ 13.2, 2.1 Hz, 1H), 2.31–2.27 (m, CDCl3): d 7.23 (d, J ¼ 8.0 Hz, 2H), 7.09 (d, J ¼ 7.9 Hz, 2H), 5.31 (s,
1H), 2.08–2.04 (m, 1H), 1.91 (s, 3H), 1.83–170 (m, 3H), 1.51 (s, 1H), 4.52 (d, J ¼ 10.56 Hz, 1H), 3.44 (td, 1H, J ¼ 10.4, 4.2 Hz), 3.09
3H), 1.24–0.97 (m, 4H), 0.95 (d, J ¼ 6.5 Hz, 3H). 13C NMR (75 (dd, J ¼ 13.9, 1.7 Hz, 1H), 2.30 (s, 3H), 2.02 (s, 3H), 2.04–1.93 (m,
MHz, CDCl3): d 169.5, 139.7, 133.3, 132.9, 127.9, 127.5, 125.8, 2H), 1.76–1.71 (m, 2H), 1.45–1.40 (m, 1H), 1.43 (s, 3H), 1.36–1.01
125.5, 124.6, 124.4, 76.0, 75.8, 55.2, 47.7, 45.5, 41.6, 34.4, 31.4, (m, 4H), 0.97 (d, J ¼ 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
24.7, 23.6, 22.1, 18.9. IR (CHCl3): 3312.4, 2925.7, 2858.4, 1658.8, 169.7, 139.4, 136.8, 128.9, 125.8, 76.7, 53.9, 50.8, 42.8, 41.6, 34.4,
1548.3 cmꢀ1. ESI (MS): m/z ¼ 374 [M + Na]+. Anal. calcd for 31.3, 24.8, 24.6, 23.0, 22.1, 21.1. IR (CHCl3): 3338.9, 2948.4, 2924.9,
1
C
3.97.
23H29NO2: C 78.59, H 8.32, N 3.99; found: C 78.55, H 8.36, N 2869.3, 1655.2, 1534.7 cmꢀ1. ESI (MS): m/z ¼ 338 [M + Na]+.
N-[2-(4-Isopropyl-phenyl)-4,7-dimethyl-octahydro-chromen-4-
N-(4,7-Dimethyl-2-naphthalen-2-yl-octahydro-chromen-4-yl)- yl]-acetamide (3e). White solid, m.p. 186.3 ꢁC. [a]D20 ¼ +4.0 (c
acetamide (4b). Semisolid. [a]2D0 ¼ +25.0 (c 0.2). H NMR (300 0.16). 1H NMR (300 MHz, CDCl3) d 7.28 (d, J ¼ 6.4 Hz, 2H), 7.17–
1
MHz, CDCl3): d 7.82–7.77 (m, 4H), 7.50–7.39 (m, 3H), 5.35 (s, 7.14 (d, J ¼ 8.1 Hz, 2H), 5.23 (s, 1H), 4.50 (dd, J ¼ 11.6, 1.7 Hz,
1H), 4.73 (d, J ¼ 10.6 Hz, 1H), 3.52 (td, J ¼ 13.9, 1.6 Hz, 1H), 3.20 1H), 3.42 (td, J ¼ 10.0, 3.9 Hz, 1H), 2.88 (m, 1H), 2.39 (dd, J ¼
(dd, J ¼ 13.8, 1.8 Hz, 1H), 2.07 (s, 3H), 2.05–1.48 (m, 4H), 1.38– 13.2, 2.0 Hz, 1H), 2.23 (m, 1H), 2.02 (m, 1H), 1.91 (s, 3H), 1.75
1.19 (m, 4H), 1.25 (s, 3H), 0.88 (d, J ¼ 7.1 Hz, 3H), 0.87–0.85 (m, (m, 3H), 1.46 (s, 3H), 1.21 (d, J ¼ 6.8 Hz, 6H), 1.14–0.98 (m, 4H),
1H). 13C NMR (75 MHz, CDCl3): d ¼ 169.8, 139.9, 133.3, 132.8, 0.95 (d, J ¼ 6.47 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 169.5,
127.9, 127.8, 127.5, 125.8, 125.5, 124.3, 124.2, 77.2, 74.9, 53.9, 148.0, 139.6, 126.3, 126.1, 75.9, 75.6, 55.2, 47.7, 45.4, 41.6, 34.4,
50.7, 42.8, 41.5, 34.4, 31.3, 29.7, 24.5, 22.9, 22.1. IR (CHCl3): 33.8, 31.3, 24.6, 24.06, 24.02, 23.6, 22.1, 18.9. IR (CHCl3): 3319.4,
3337.9, 2926.7, 2868.8, 1656.0, 1532.7 cmꢀ1. ESI (MS): m/z ¼ 374 2957.4, 2926.7, 2869.2, 1652.7, 1540.2 cmꢀ1. ESI (MS): m/z ¼ 366
[M + Na]+.
[M + Na]+. Anal. calcd for C22H33NO2: C 76.92, H 9.68, N 4.08;
N-[2-(4-Methoxy-phenyl)-4,7-dimethyl-octahydro-chromen-4-yl]- found: C 76.87, H 9.64, N 4.10.
acetamide (3c). White solid; m.p. 199.6 ꢁC. [a]D20 ¼ ꢀ2.0 (c 0.16).
N-[2-(4-Isopropyl-phenyl)-4,7-dimethyl-octahydro-chromen-4-
1H NMR (300 MHz, CDCl3): d 7.29 (d, J ¼ 7.6 Hz, 2H), 6.86 (m, yl]-acetamide (4e). Gummy liquid. [a]2D0 ¼ +37.0 (c 0.3). 1H NMR
J ¼ 7.6 Hz, 2H), 5.26 (s, 1H), 4.48 (dd, J ¼ 11.6, 1.9 Hz, 1H) 3.77 (300 MHz, CDCl3): d 7.26 (d, J ¼ 6.2 Hz, 2H), 7.14 (d, J ¼ 8.0 Hz,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 22387–22397 | 22393

View Article Online
RSC Advances
Paper
2H), 5.32 (s, 1H), 4.52 (d, 1H, J ¼ 10.6 Hz), 3.44 (td, J ¼ 10.2, 4.1 7.13 (m, 1H), 5.30 (s, 1H), 4.48 (d, J ¼ 11.3 Hz, 1H), 3.44 (td, J ¼
Hz, 1H), 3.09 (dd, J ¼ 13.9, 1.4 Hz, 1H), 2.88 (m, 1H), 2.02 (s, 3H), 10.5, 4.2 Hz, 1H), 3.17 (dd, J ¼ 13.8, 1.8 Hz, 1H), 2.03 (s, 3H),
1.96–1.77 (m, 4H), 1.49–1.48 (m, 1H), 1.43 (s, 3H), 1.22 (d, J ¼ 6.9 2.00–1.92 (m, 2H), 1.62 (s, 3H), 1.50–1.45 (m, 3H), 1.36–1.00 (m,
Hz, 6H), 1.15–0.98 (m, 4H), 0.96 (d, J ¼ 6.4 Hz, 3H). 13C NMR (75 4H), 0.96 (d, J ¼ 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 169.6,
MHz, CDCl3): d ¼ 169.7, 147.9, 139.6, 126.2, 125.9, 74.8, 53.9, 142.8, 127.8, 125.2, 77.0, 74.8, 73.5, 53.8, 50.5, 42.5, 41.4, 34.3,
50.7, 42.5, 41.5, 34.4, 33.8, 31.3, 24.8, 24.5, 24.06, 24.03, 22.9, 31.2, 24.7, 24.5, 22.8, 22.0. IR (CHCl3): 3327.5, 2927.1, 2868.9,
22.1. IR (CHCl3): 3338.2, 2957.8, 2927.0, 2870.1, 1652.2, 1538.4 1655.7, 1537.7 cmꢀ1. ESI (MS): m/z ¼ 393 [M + Na]+.
cmꢀ1; ESI (MS): m/z ¼ 366 [M + Na]+. HRMS (APCI) calcd for
N-[2-(4-Bromo-phenyl)-4,7-dimethyl-octahydro-chromen-4-yl]-
acetamide (3i). White solid; m.p. 238.0 ꢁC. [a]D20 ¼ ꢀ1.0 (c 0.2). 1H
C
22H34NO2 (M + H)+ requires 344.2584; found 344.2602.
N-[4,7-Dimethyl-2-(3-nitro-phenyl)-octahydro-chromen-4-yl]- NMR (300 MHz, CDCl3): d 7.43 (d, J ¼ 8.4 Hz, 2H), 7.24 (d, J ¼ 8.4
acetamide (3f and 4f). Gummy liquid. 1H NMR (300 MHz, Hz, 2H), 5.30 (s, 1H), 4.48 (dd, J ¼ 11.7, 1.8 Hz, 1H), 3.44 (td, J ¼
CDCl3): d 8.25 (s, 1H), 8.11 (dd, J ¼ 8.1, 0.9 Hz, 1H), 7.70–7.62 (m, 10.3, 4.1 Hz, 1H), 2.37 (dd, 1H, J ¼ 13.2, 2.1 Hz), 2.17–2.03 (m,
1H), 7.50–7.43 (m, 1H), 5.34 (s, 1H), 4.66 (d, J ¼ 10.2 Hz, 1H), 3.50 2H), 1.91 (s, 3H), 1.75–1.70 (m, 3H), 1.46 (s, 3H), 1.18–0.98 (m,
(td, J ¼ 10.4, 4.2 Hz, 1H), 2.46 (dd, J ¼ 13.2, 1.9 Hz, 1H), 2.20–2.05 4H), 0.95 (d, J ¼ 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 169.5,
(m, 2H), 1.92 (s, 3H), 1.81–1.74 (m, 4H), 1.49 (s, 3H), 1.26–0.99 (m, 141.4, 131.3, 127.8, 121.0, 77.2, 75.9, 75.0, 55.0, 47.5, 45.4, 41.5,
3H), 0.97 (d, J ¼ 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): d ¼ 169.8, 34.3, 31.3, 24.6, 23.5, 22.1, 18.9. IR (CHCl3): 3307.4, 2948.6,
148.2, 144.7, 132.2, 129.2, 122.3, 121.0, 76.0, 73.7, 54.9, 47.3, 45.4, 2925.6, 2858.9, 1649.8, 1549.7 cmꢀ1. ESI (MS): m/z ¼ 403 [M +
41.4, 34.2, 31.3, 24.7, 23.4, 22.1, 18.8. IR (CHCl3): 3310.1, 2927.9, Na]+. Anal. calcd for C19H26BrNO2: C 60.00, H 6.89, N 3.68; found:
2867.9, 1655.9, 1530.9 cmꢀ1. ESI (MS): m/z ¼ 369 [M + Na]+. (d C 59.96, H 6.84, N 3.73.
Values given here for the major isomer present in the spectrum of
N-[2-(4-Bromo-phenyl)-4,7-dimethyl-octahydro-chromen-4-yl]-
the mixture of 3f & 4f). HRMS (APCI) calcd for C19H27N2O4 (M + acetamide (4i). Gummy liquid. [a]2D0 ¼ +26.0 (c 0.2). 1H NMR (300
H)+ requires 347.1965; found 347.1987.
MHz, CDCl3): d 7.36 (d, J ¼ 8.3 Hz, 2H), 7.17–7.12 (d, J ¼ 8.3 Hz,
N-[2-(4-Chloro-phenyl)-4,7-dimethyl-octahydro-chromen-4-yl]- 2H), 5.21 (s, 1H), 4.45 (dd, J ¼ 10.3, 1.8 Hz, 1H), 3.37 (td, J ¼ 10.4,
acetamide (3g). White solid; m.p. 219.2 ꢁC. [a]D20 ¼ +2.0 (c 0.16). 4.2 Hz, 1H) 3.07 (dd, J ¼ 13.9, 1.8 Hz, 1H) 1.96 (s, 3H), 1.89–1.38
1H NMR (300 MHz, CDCl3): d 7.30–7.24 (m, 4H), 5.31 (s, 1H), 4.50 (m, 5H), 1.34 (s, 3H), 1.31–0.90 (m, 4H), 0.88 (d, J ¼ 6.4 Hz, 3H).
(dd, J ¼ 11.7, 2.0 Hz, 1H), 3.45 (td, J ¼ 10.4, 4.1 Hz, 1H), 2.37 (dd, 13C NMR (75 MHz, CDCl3): d 169.8, 141.5, 131.2, 127.8, 127.5,
J ¼ 13.3, 2.2 Hz, 1H), 2.18–2.03 (m, 2H), 1.91 (s, 3H), 1.78–1.70 120.9, 77.2, 74.8, 74.1, 53.8, 50.6, 42.6, 41.4, 34.3, 31.2, 24.8, 24.5,
(m, 3H), 1.45 (s, 3H), 1.17–0.97 (m, 4H), 0.95 (d, J ¼ 6.48 Hz, 3H); 22.8, 22.1. IR (CHCl3): 3337.0, 2948.9, 2925.7, 2868.5, 1655.6,
13C NMR (75 MHz, CDCl3): d 169.5, 140.9, 132.9, 128.3, 127.4, 1538.4 cmꢀ1. ESI (MS): m/z ¼ 403 [M + Na]+.
77.0, 75.9, 75.0, 55.0, 47.5, 45.4, 41.5, 34.3, 31.3, 24.6, 23.5, 22.1,
N-(2-Furan-2-yl-4,7-dimethyl-octahydro-chromen-4-yl)-acet-
18.9. IR (CHCl3): 3308.1, 2926.0, 2859.3, 1650.3, 1548.0 cmꢀ1. ESI amide (3j). White solid, m.p. 221.2 ꢁC. [a]2D0 ¼ ꢀ46.0 (c 0.16). 1H
(MS): m/z ¼ 359 [M + Na]+. Anal. calcd for C19H26ClNO2: C 67.94, NMR (300 MHz, CDCl3): d 7.35 (s, 1H), 6.31–6.26 (m, 2H), 5.80 (s,
7.80, N 4.17; found: C 67.89, H 7.85, N 4.12.
1H), 4.60 (dd, J ¼ 10.4, 3.5 Hz, 1H), 3.47 (td, J ¼ 10.4, 4.2 Hz, 1H),
N-[2-(4-Chloro-phenyl)-4,7-dimethyl-octahydro-chromen-4-yl]- 2.45–2.41 (m, 2H), 2.04–1.99 (m, 1H), 1.95 (s, 3H), 1.75–1.69 (m,
1
acetamide (4g). Gummy liquid. [a]2D0 ¼ +12.0 (c 0.08). H NMR 3H), 1.43 (s, 3H), 1.25–0.95 (m, 4H), 0.93 (d, J ¼ 6.5 Hz, 3H). 13
C
(300 MHz, CDCl3): d 7.26 (s, 4H), 5.27 (s, 1H), 4.54 (dd, J ¼ 11.4, NMR (75 MHz, CDCl3): d ¼ 169.6, 154.3, 142.0, 110.0, 106.7,
1.5 Hz, 1H), 3.47 (td, J ¼ 10.4, 6.2 Hz, 1H), 3.14 (dd, J ¼ 13.9, 1.6 75.9, 69.1, 54.7, 47.6, 41.4, 34.2, 31.3, 29.6, 23.5, 22.6, 22.0, 18.7.
Hz, 1H), 2.03 (s, 3H), 1.96–1.50 (m, 4H), 1.42 (s, 3H), 1.39–0.93 IR (CHCl3): 3356.7, 2950.8, 2925.3, 2855.4, 1668.5, 1539.6 cmꢀ1
.
(m, 5H), 0.98 (d, J ¼ 6.4 Hz, 3H). IR (CHCl3): 3335.9, 2925.8, ESI (MS): m/z ¼ 314 [M + Na]+. Anal. calcd for C17H25NO3: C
2855.1, 1655.8, 1534.0 cmꢀ1 13C NMR (75 MHz, CDCl3): d 169.8, 70.07, H 8.65, N 4.81; found: C 70.01, H 8.69, N 4.76.
.
140.9, 132.7, 128.3, 127.2, 77.2, 74.8, 74.1, 53.8, 50.6, 42.6, 41.4,
N-(2-Furan-2-yl-4,7-dimethyl-octahydro-chromen-4-yl)-acet-
amide (4j). White solid; m.p. 216.0 ꢁC. [a]D20 ¼ +34.0 (c 0.16). 1H
34.3, 31.2, 24.8, 24.5, 22.8, 22.0; ESI (MS): m/z ¼ 359 [M + Na]+.
N-[2-(3,4-Dichloro-phenyl)-4,7-dimethyl-octahydro-chromen- NMR (300 MHz, CDCl3): d 7.36 (d, J ¼ 1.0 Hz, 1H), 6.30–6.24 (m,
20
ꢁ
4-yl]-acetamide (3h). White solid. m.p. 213.2 C. [a]D ¼ +4.0 (c 2H), 5.26 (s, 1H), 4.62 (dd, J ¼ 11.8, 1.5 Hz, 1H), 3.45 (td, J ¼
0.2). 1H NMR (300 MHz, CDCl3): d 7.46 (d, J ¼ 1.9 Hz, 1H), 7.35 10.4, 4.2 Hz, 1H), 3.12 (dd, J ¼ 13.8, 1.7 Hz, 1H), 1.99 (s, 3H),
(m, 1H), 7.19 (dd, J ¼ 8.3, 1.9 Hz, 1H), 5.25 (s, 1H), 4.49 (dd, J ¼ 2.00–1.93 (m, 1H), 1.77–1.66 (m, 2H), 1.48 (s, 3H), 1.25–0.88 (m,
11.9, 1.9 Hz, 1H), 3.44 (td, J ¼ 10.3, 4.1 Hz, 1H), 2.39 (dd, J ¼ 13.3, 6H), 0.90 (d, J ¼ 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 169.5,
2.2 Hz, 1H), 2.15–2.10 (m, 3H), 1.92 (s, 3H), 1.75–1.70 (m, 2H), 154.2, 142.1, 110.0, 106.8, 77.2, 68.5, 50.5, 41.3, 38.1, 34.2, 31.2,
1.45 (s, 3H), 1.19–1.08 (m, 4H), 0.96 (d, J ¼ 6.5 Hz, 3H). 13C NMR 29.7, 24.7, 24.5, 22.9, 22.0. IR (CHCl3): 3338.2, 2925.7, 2854.4,
(75 MHz, CDCl3): d 169.6, 142.7, 132.2, 131.0, 130.1, 128.0, 125.4, 1655.4, 1535.8 cmꢀ1. ESI (MS): m/z ¼ 314 [M + Na]+.
75.9, 74.4, 54.9, 47.3, 45.3, 41.4, 34.3, 31.3, 24.6, 23.5, 22.1, 18.8.
N-(4,7-Dimethyl-2-thiophen-2-yl-octahydro-chromen-4-yl)-acet-
IR (CHCl3): 3301.1, 2925.5, 2859.0, 1650.1, 1550.7 cmꢀ1. ESI (MS): amide (3k). White solid; m.p. 216.0 ꢁC. [a]2D0 ¼ ꢀ18.0 (c 0.16). 1H
m/z ¼ 393 [M + Na]+. Anal. calcd for C19H25Cl2NO2: C 61.62, H NMR (300 MHz, CDCl3): d 7.21–7.20 (d, J ¼ 4.8 Hz, 1H), 6.97–
6.80, N 3.78; found: C 61.58, H 6.76, N 3.84.
6.91 (m, 2H), 5.59 (s, 1H), 4.78 (d, J ¼ 10.5 Hz, 1H), 3.49 (td, J ¼
N-[2-(3,4-Dichloro-phenyl)-4,7-dimethyl-octahydro-chromen- 10.3, 4.0 Hz, 1H), 2.59 (dd, J ¼ 13.1, 1.6 Hz, 1H), 2.31 (m, 1H),
1
4-yl]-acetamide (4h). Semisolid. [a]2D0 ¼ +24.0 (c 0.16). H NMR 1.98 (s, 3H), 2.04–1.96 (m, 1H), 1.75–1.70 (m, 3H), 1.47 (s, 3H),
(300 MHz, CDCl3): d 7.45 (s, 1H), 7.42 (d, J ¼ 8.1 Hz, 1H), 7.19– 1.25–1.09 (m, 4H), 0.94 (d, J ¼ 6.4 Hz, 3H). 13C NMR (75 MHz,
22394 | RSC Adv., 2014, 4, 22387–22397
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
CDCl3): d ¼ 169.8, 145.4, 126.3, 124.5, 123.6, 76.0, 71.5, 55.0, m/z ¼ 352 [M + Na]+. HRMS (APCI) calcd For C21H32NO2 (M + H)+
47.7, 45.2, 41.4, 36.6, 34.3, 31.3, 24.6, 23.5, 22.1. IR (CHCl3): requires 330.2428; found 330.2453.
3307.8, 2948.8, 2926.1, 2858.9, 1655.0, 1548.1 cmꢀ1. ESI (MS):
N-(2-Isopropyl-4,7-dimethyl-octahydro-chromen-4-yl)-acet-
m/z ¼ 330 [M + Na]+. Anal. calcd for C17H25NO2S: C 66.41, H amide (3n). Gummy liquid. [a]2D0 ¼ ꢀ26.0 (c 0.2). 1H NMR (300
8.20, N 4.56; found: C 66.45, H 8.16, N 4.60.
MHz, CDCl3): d 5.25 (s, 1H), 3.20–3.07 (m, 2H), 2.22 (d, J ¼ 12.9
N-(4,7-Dimethyl-2-thiophen-2-yl-octahydro-chromen-4-yl)- Hz, 1H), 1.93 (s, 3H), 1.81–1.35 (m, 7H), 1.25 (s, 3H), 1.06–0.99
1
acetamide (4k). Gummy liquid. [a]2D0 ¼ +25.0 (c 0.2). H NMR (m, 3H), 0.93 (d, J ¼ 6.6 Hz, 6H), 0.88 (d, J ¼ 6.4 Hz, 3H). 13C
(300 MHz, CDCl3): d 7.21–7.20 (m, 1H), 6.96–6.91 (m, 2H), 5.27 NMR (75 MHz, CDCl3): d 169.7, 78.3, 75.3, 55.2, 48.2, 41.6, 40.3,
(s, 1H), 4.81 (d, J ¼ 10.6 Hz, 1H), 3.47 (td, J ¼ 10.4, 4.2 Hz, 1H), 34.4, 32.9, 31.3, 29.6, 24.6, 23.5, 22.1, 18.9, 18.3. IR (CHCl3):
3.25 (dd, J ¼ 13.7, 1.4 Hz, 1H), 2.06–1.83 (m, 2H), 2.01 (s, 3H), 3306.8, 2926.8, 2856.2, 1645.0, 1553.8 cmꢀ1. ESI (MS): m/z ¼ 290
1.63–1.59 (m, 3H), 1.46 (s, 3H), 1.25–0.96 (m, 4H), 0.96 (d, 3H, [M + Na]+, Anal. calcd for C16H29NO2: C 71.86, H 10.93, N 5.24;
J ¼ 6.4 Hz). 13C NMR (75 MHz, CDCl3): d 169.9, 145.4, 126.3, found: C 71.85, H 10.91, N 5.22. HRMS (APCI) calcd for
124.4, 123.6, 74.9, 71.0, 53.8, 50.5, 42.1, 41.3, 36.6, 34.3, 31.2,
24.6, 22.9, 22.0. IR (CHCl3): 3334.5, 2926.3, 2868.8, 1655.4,
1536.0 cmꢀ1. ESI (MS): m/z ¼ 330 [M + Na]+.
C
16H30NO2 (M + H)+ requires 268.2271; found 268.2279.
N-(2-Cyclohexyl-4,7-dimethyl-octahydro-chromen-4-yl)-acet-
1
amide (3o). Gummy liquid. [a]2D0 ¼ ꢀ25.0 (c 0.2). H NMR (300
N-(2-Ethyl-4,7-dimethyl-octahydro-chromen-4-yl)-acetamide MHz, CDCl3): d 5.22 (s, 1H), 3.18–3.13 (m, 2H), 2.20 (d, J ¼ 12.4
20
1
ꢁ
(3l). White solid. m.p. 140.7 C. [a]D ¼ ꢀ26.0 (c 0.2). H NMR Hz, 1H), 1.92 (s, 3H), 1.78–1.35 (m, 12H), 1.34 (s, 3H), 1.32–0.94
(300 MHz, CDCl3): d 5.22 (s,1H), 3.35–3.31 (m, 1H), 3.23–3.20 (m, 8H), 0.92 (d, J ¼ 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
(m, 1H), 2.24 (dd, J ¼ 11.4, 1.6 hz, 1H), 1.98–1.88 (m, 1H), 1.93 169.5, 77.7, 77.0, 75.3, 55.1, 48.3, 42.8, 41.6, 40.6, 34.4, 31.3, 29.2,
(s, 3H), 1.76–1.69 (m, 4H), 1.66–1.41 (m, 3H), 1.36 (s, 3H), 1.07– 28.6, 26.5, 26.1, 24.7, 23.5, 22.1, 18.9. IR (CHCl3): 3308.8, 2925.5,
1.03 (m, 3H), 0.93 (m, 6H); 13C NMR (75 MHz, CDCl3): d 169.5, 2853.7, 1650.3, 1551.0 cmꢀ1; ESI (MS): m/z ¼ 309 [M + 2]+.
77.2, 74.8, 54.9, 48.3, 43.3, 41.6, 34.4, 31.3, 29.0, 24.7, 23.5, 22.1,
N-(2-Cyclohexyl-4,7-dimethyl-octahydro-chromen-4-yl)-acet-
18.9, 9.9. IR (CHCl3): 3307.7, 2949.2, 2926.2, 2856.8, 1655.4, amide (4o). White solid; m.p. 120.2 ꢁC. [a]D20 ¼ +37.0 (c 0.3). 1H
1551.5 cmꢀ1. ESI (MS): m/z ¼ 276 [M + Na]+. Anal. calcd for NMR (300 MHz, CDCl3): d 5.19 (s, 1H), 3.19–3.15 (m, 2H), 2.83
C
5.58.
15H27NO2: C 71.10, H 10.74, N 5.53; found: C 71.06, H 10.69, N (dd, J ¼ 13.6, 1.2 Hz,. 1H), 1.96 (s, 3H), 1.90–1.88 (m, 3H), 1.73–
1.64 (m, 5H), 1.40 (s, 3H), 1.18–0.90 (m, 12H), 0.92 (d, J ¼ 6.4 Hz,
N-(2-Ethyl-4,7-dimethyl-octahydro-chromen-4-yl)-acetamide 3H). 13C NMR (75 MHz, CDCl3): d 169.6, 77.2, 74.5, 53.7, 51.0,
20
1
ꢁ
(4l). White solid. m.p. 136.5 C. [a]D ¼ +35.0 (c 0.3). H NMR 42.4, 41.5, 37.6, 34.4, 31.2, 29.0, 28.9, 28.6, 26.5, 26.1, 24.7, 22.9,
(300 MHz, CDCl3): d 5.20 (s, 1H), 3.33 (m, 1H), 3.23 (m, 1H), 2.81 22.1. IR (CHCl3): 3339.2, 2926.0, 2853.1, 1654.7, 1535.5 cmꢀ1
.
(dd, J ¼ 13.7, 1.5 Hz, 1H), 1.97 (s, 3H), 1.96–1.80 (m, 1H), 1.74 ESI (MS): m/z ¼ 309 [M + 2]+. Anal. calcd for C19H33NO2: C 74.22,
(m, 2H), 1.49–1.43 (m, 2H), 1.41 (s, 3H), 1.20–1.01 (m, 3H), 0.96– H 10.82, N 4.56; found: C 74.18, H 10.77, N 4.60.
0.88 (m, 9H); 13C NMR (75 MHz, CDCl3): d 169.6, 77.2, 74.1, 53.6,
N-(4,7-Dimethyl-2-styryl-octahydro-chromen-4-yl)-acetamide
20
1
ꢁ
50.9, 41.6, 40.4, 34.3, 31.2, 28.6, 24.7, 24.5, 22.9, 22.0, 9.9. IR (7). White solid; m.p. 153.2 C. [a]D ¼ ꢀ36.0 (c 0.3). H NMR
(CHCl3): 3337.0, 2926.6, 2871.9, 1650.3, 1538.0 cmꢀ1. ESI (MS): (300 MHz, CDCl3): d 7.36–7.18 (m, 5H), 6.60 (d, 1H, J ¼ 16.0 Hz),
m/z ¼ 276 [M + Na]+. Anal. calcd for C15H27NO2: C 71.10, H 6.21 (dd, J ¼ 16.0, 6.1 Hz, 1H), 5.32 (s, 1H), 4.18 (m, 1H), 3.38 (td,
10.74, N 5.53; found: C 71.15, H 10.70, N 5.48.
J ¼ 10.0, 6.4 Hz, 1H), 2.34 (dd, J ¼ 11.2, 1.9 Hz, 1H), 2.06–1.99
N-(4,7-Dimethyl-2-phenethyl-octahydro-chromen-4-yl)-acet- (m, 2H), 1.94 (s, 3H), 1.73–1.68 (m, 3H), 1.42 (s, 3H), 1.25–1.06
amide (3m). Gummy liquid. [a]2D0 ¼ ꢀ26.0 (c 0.2). 1H NMR (300 (m, 4H), 0.95 (d, J ¼ 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
MHz, CDCl3): d 7.29–7.25 (m, 3H), 7.18–7.14 (m, 2H), 5.30 (s, 169.6, 136.8, 130.4, 130.1, 129.9, 128.4, 127.4, 126.4, 77.2, 75.5,
1H), 3.44 (m, 1H), 3.21 (td, J ¼ 10.1, 3.9 Hz, 1H), 2.70 (m, 2H), 74.1, 54.8, 47.7, 43.5, 41.5, 34.3, 31.3, 24.6, 23.5, 22.1, 18.8. IR
2.20 (dd, J ¼ 12.8, 1.5 Hz, 1H), 1.98–1.90 (m, 2H), 1.93 (s, 3H), (CHCl3): 2926.4, 2867.0, 1655.2, 1541.1 cmꢀ1. ESI (MS): m/z ¼
1.88–1.64 (m, 5H), 1.31 (s, 3H), 1.21–0.92 (m, 4H), 0.94 (d, J ¼ 350 [M + Na]+. Anal. calcd for C21H29NO2: C 77.02, H 8.93, N
6.45 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 169.9, 142.1, 128.4, 4.28; found: C 77.06, H 8.89, N 4.24.
128.2, 125.6, 75.4, 72.4, 55.1, 48.1, 43.5, 41.6, 37.6, 34.3, 31.7,
N-(4,7-Dimethyl-2-styryl-octahydro-chromen-4-yl)-acetamide
31.3, 24.6, 24.5, 23.5, 23.4, 22.1, 18.9. IR (CHCl3): 3307.3, 2925.8, (8). Semisolid. [a]2D0 ¼ +37.0 (c 0.3). 1H NMR (300 MHz, CDCl3): d
2859.0, 1650.3, 1551.1 cmꢀ1; ESI (MS): m/z ¼ 352 [M + Na]+. 7.36–7.17 (m, 5H), 6.60 (d, J ¼ 16.0 Hz, 1H), 6.21 (dd, J ¼ 16.0, 5.6
HRMS (APCI) calcd for C21H32NO2 (M + H)+ requires 330.2428; Hz, 1H), 5.33 (s, 1H), 4.21 (m, 1H), 3.38 (td, J ¼ 10.4, 4.1 Hz, 1H),
found 330.2450.
3.00 (dd, J ¼ 3.8, 1.6 Hz, 1H), 2.01–1.90 (m, 1H), 1.93 (s, 3H), 1.78–
N-(4,7-Dimethyl-2-phenethyl-octahydro-chromen-4-yl)-acet- 1.45 (m, 3H), 1.44 (s, 3H), 1.41–1.00 (m, 5H), 0.96 (d, J ¼ 6.4 Hz,
amide (4m). Gummy liquid. [a]2D0 ¼ +36.0 (c 0.3). 1H NMR (300 3H). 13C NMR (75 MHz, CDCl3): d 169.9, 136.9, 130.1, 129.9,
MHz, CDCl3): d 7.28–7.26 (m, 2H), 7.18–7.13 (m, 3H), 5.22 (s, 128.4, 127.3, 126.4, 77.3, 74.3, 73.2, 53.6, 50.6, 41.4, 40.7, 34.3,
1H), 3.41 (m, 1H), 3.21–3.19 (m, 1H), 2.86 (d, J ¼ 12.8 Hz, 1H), 31.2, 24.7, 24.5, 23.4, 22.8, 22.1. IR (CHCl3): 2927.1, 2869.7,
2.72–2.67 (m, 2H), 1.95 (s, 3H), 1.97–1.69 (m, 6H), 1.42 (s, 3H), 1656.0, 1532.2 cmꢀ1. ESI (MS): m/z ¼ 328 [M + 1]+. HRMS (APCI)
1.21–1.02 (m, 5H), 0.96 (d, J ¼ 6.45 Hz, 3H). 13C NMR (75 MHz, calcd for C21H30NO2 (M + H)+ requires 328.2271; found 328.2282.
CDCl3): d 169.8, 142.1, 128.4, 127.4, 126.4, 74.3, 73.2, 53.5, 50.6,
N-(4,7-Dimethyl-2-styryl-octahydro-chromen-4-yl)-acetamide
41.4, 40.7, 40.5, 37.2, 34.3, 31.3, 24.7, 24.5, 22.9, 22.1. IR (10). Semisolid. [a]D20
¼
+24.0 (c 0.16). 1H NMR (300
(CHCl3): 3335.9, 2925.4, 2867.5, 1650.2, 1539.7 cmꢀ1. ESI (MS): MHz, CDCl3): d 7.77 (d, J ¼ 7.2 Hz, 2H) 7.55–7.43 (m, 3H),
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 22387–22397 | 22395

View Article Online
RSC Advances
Paper
7.27–7.24 (m, 2H), 6.84 (d, J ¼ 8.5 Hz, 2H), 6.06 (s, 1H), 4.58 (d,
J ¼ 11.1 Hz, 1H), 3.77 (s, 3H), 3.57 (td, J ¼ 10.4, 4.1 Hz, 1H),
3.23 (d, J ¼ 13.6 Hz, 1H), 2.10–2.03 (m, 2H), 1.84 (m, 1H), 1.80–
1.45 (m, 2H), 1.56 (s, 3H), 1.40–0.87 (m, 4H), 0.99 (d, J ¼ 6.4
Hz, 3H). 13C NMR (75 MHz, CDCl3): d 169.9, 136.9, 130.1,
129.9, 128.4, 127.3, 126.4, 77.3, 74.3, 73.2, 53.6, 50.6, 41.4,
40.7, 34.3, 31.2, 24.7, 24.5, 23.4, 22.8, 22.1. ESI (MS): m/z ¼ 328
[M + 1]+.
G. S. Viswanathan, J. Yang and C. J. Li, Org. Lett., 1999, 1,
993; (j) J. S. Yadav, B. V. Subba Reddy,
G. G. K. S. Narayana Kumar and T. Swamy, Tetrahedron
Lett., 2007, 48, 2205.
5 (a) G. H. Posner, Chem. Rev., 1986, 86, 831; (b) T.-L. Ho,
Tandem Organic Reactions, Wiley-Interscience, New York,
1992; (c) N. Hall, Science, 1994, 266, 32; (d) L. F. Tietze,
Chem. Rev., 1996, 96, 115; (e) J. Montgomery, Angew. Chem.,
Int. Ed., 2004, 43, 3890; (f) E. Negishi, C. Coperet, S. Ma,
S. Y. Liou and F. Liu, Chem. Rev., 1996, 96, 365; (g)
T. Miura and M. Murakami, Chem. Commun., 2007, 217; (h)
K. Agapiou, D. F. Cauble and M. J. Krische, J. Am. Chem.
Soc., 2004, 126, 4528; (i) K. Subburaj and J. Montgomery, J.
Am. Chem. Soc., 2003, 125, 11210; (j) H. C. Guo and
J. A. Ma, Angew. Chem., Int. Ed., 2006, 45, 354; (k)
D. Enders, M. R. M. Huttl, C. Grondal and G. Raabe,
Nature, 2006, 441, 861; (l) S. Cabrera, J. Alemen, P. Bolze,
S. Bertelsen and K. A. Jorgensen, Angew. Chem., Int. Ed.,
2008, 47, 121; (m) O. Penon, A. Carlone, A. Mazzanti,
M. Locatelli, L. Sambri, G. Bartoli and P. Melchiorre,
Chem.–Eur. J., 2008, 14, 4788.
Acknowledgements
We are grateful to Department of Science & Technology, New
Delhi, for nancial support to this work and for fellowship of
BS. We thank the Director, CSIR-NEIST, Jorhat, for his keen
interest and encouragement.
References
1 Y. J. Class and P. DeShong, Chem. Rev., 1995, 95, 1843;
R. D. Norcross and I. Paterson, Chem. Rev., 1995, 95, 2041;
´
I. E. Marko and D. J. Bayston, Synthesis, 1996, 297;
S. D. Rychnovsky, G. Yang, Y. Hu and U. D. Khire, J. Org.
Chem., 1997, 62, 3022; A. B. Smith, III, P. R. Verhoest,
K. P. Minbiole and M. Schelhaas, J. Am. Chem. Soc., 2001,
123, 4834; D. J. Kopecky and S. D. Rychnovsky, J. Am.
Chem. Soc., 2001, 123, 8420; Y. Wang, J. Janjic and
S. A. Kozmin, J. Am. Chem. Soc., 2002, 124, 13670;
D. L. Aubele, S. Wan and P. E. Floreancig, Angew. Chem.,
Int. Ed., 2005, 44, 3485; X.-F. Yang, M. Wang, Y. Zhang and
C.-J. Li, Synlett, 2005, 1912; X. Tian, J. J. Jaber and
S. D. Rychnovsky, J. Org. Chem., 2006, 71, 3176;
K. B. Bahnck and S. D. Rychnovsky, Chem. Commun., 2006,
2388; K. C. Nicolaou and E. J. Sorensen, Classics in Total
Synthesis, VCH, Weinham, 1996.
6 J. S. Yadav, Y. Jayasudhan Reddy, P. Adi Narayana Reddy and
B. V. Subba Reddy, Org. Lett., 2013, 15, 546, and references
cited therein.
7 (a) V. Michelet and J.-P. Genet, Curr. Org. Chem., 2005, 9, 405;
(b) G. Hoee, H. Steinmetz, K. Gerth and H. Reichenbach,
Liebigs Ann. Chem., 1991, 941; (c) Y. Suhara, Y. Yamaguchi,
B. Collins, R. L. Schnaar, M. Yanagishita, J. E. K. Hildreth,
I. Shimada and Y. Ichikawa, Bioorg. Med. Chem., 2002, 10,
1999; (d) A. Dondoni, A. Boscarato and A. Marra,
Tetrahedron: Asymmetry, 1994, 5, 2209; (e) S. Ciccotosto and
M. von Itzstein, Tetrahedron Lett., 1995, 36, 5405; (f)
S. Sabesan, S. Neira and Z. Wasserman, Carbohydr. Res.,
1995, 267, 239; (g) B. B. Snider and N. A. Hawryluk, Org.
Lett., 2000, 2, 635–638.
8 (a) H. Sakata and H. Yasukawa, Jpn. Kokai Tokkyo Koho, 2003,
42; (b) G. J. McGarvey, M. W. Stepanian, A. R. Bressette and
M. Sabat, Org. Lett., 2000, 2, 3453.
9 E. H. Al-Mutairi, S. R. Crosby, J. Darzi, J. R. Harding,
R. A. Hughes, C. D. King, T. J. Simpson, R. W. Smith and
C. L. Willis, Chem. Commun., 2001, 835.
2 (a) E. Arundale and L. A. Mikeska, Chem. Rev., 1952, 51, 505–
555; (b) B. B. Snider, in Comprehensive Organic Synthesis, ed.
B. M. Trost, Pergamon Press, New York, 1991, vol. 2, p. 527;
(c) C. Olier, M. Kaafarani, S. Gastaldi and M. P. Bertrand,
Tetrahedron, 2010, 66, 413–445.
3 Reviews on multi-component reactions: (a) L. F. Tietze and
U. Beifuss, Angew. Chem., Int. Ed., 1993, 32, 131; (b)
L. F. Tietze, Chem. Rev., 1996, 96, 115; L. F. Tietze and 10 (a) J. S. Yadav, B. V. Subba Reddy, G. G. K. S. Narayana Kumar
N. Rackelmann, Pure Appl. Chem., 2004, 76, 1967(c)
A. Padwa, Pure Appl. Chem., 2004, 76, 1933; J. Zhu and
H. Bienayme, Multicomponent Reactions, Wiley, Weinheim,
2005.
and M. G. Reddy, Tetrahedron Lett., 2007, 48, 4903; (b)
J. S. Yadav, B. V. Subba Reddy, S. Aravind,
G. G. K. S. Narayana Kumar, C. Madhavi and A. C. Kunwar,
Tetrahedron, 2008, 64(13), 3025–3031.
4 (a) S. D. Rychnovsky and C. R. Thomas, Org. Lett., 2000, 2, 11 (a) U. C. Reddy, B. R. Raju, E. K. P. Kumar and A. K. Saikia, J.
1217; (b) X.-F. Yang, M. Wang, Y. Zhang and C.-J. Li,
Synlett, 2005, 1912; (c) O. L. Epstein and T. Tomislav
Rovis, J. Am. Chem. Soc., 2006, 128, 16480; (d) J. S. Yadav,
B. V. Subba Reddy, T. Maity and G. G. K. S. Narayana
Kumar, Tetrahedron Lett., 2007, 48, 7155; (e) Z. Y. Wei,
Org. Chem., 2008, 73, 1628; (b) G. Sabitha, M. Bhikshapathi,
S. Nayak, J. S. Yadav, R. Ravi and A. C. Kunwar, Tetrahedron
Lett., 2008, 49, 5727; (c) J. S. Yadav, B. V. S. Reddy, S. Aravind,
G. G. K. S. N. Kumar, C. Madhavi and A. C. Kunwar,
Tetrahedron, 2008, 64, 3025.
J. S. Li, D. Wang and T. H. Chan, Tetrahedron Lett., 1987, 12 H. Banskota, Y. Tezuka, J. K. Prasain, K. Matsushige, I. Saiki
28, 3441; (f) F. Perron and K. F. J. Albizati, Org. Chem., and S. Kadota, J. Nat. Prod., 1998, 61, 896.
1987, 52, 4130; (g) Z. Y. Wei, D. Wang, J. S. Li and 13 T. C. McKee, R. W. Fuller, C. D. Covington, J. H. Cardellina,
T. H. J. Chan, Org. Chem., 1989, 54, 5768; (h) L. Coppi,
A. Ricci and M. J. Taddei, Org. Chem., 1988, 53, 913; (i)
R. J. Gulakowski, B. L. Krepps, J. B. McMahon and
M. R. Boyd, J. Nat. Prod., 1996, 59, 754.
22396 | RSC Adv., 2014, 4, 22387–22397
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
14 (a) V. A. Ashwood, F. Cassidy, M. C. Coldwell, J. M. Evans, 16 (a) P. Srinivasan, P. T. Perumal and S. Raja, Indian J. Chem.,
T. C. Hamilton, D. R. Howlett, D. M. Smith and G. Stemp,
J. Med. Chem., 1990, 33, 2667; (b) F. Cassidy, J. M. Evans,
M. S. Hadley, A. H. Haladij, P. E. Leach and G. Stemp, J.
Med. Chem., 1992, 35, 1623.
Sect. B: Org. Chem. Incl. Med. Chem., 2011, 50, 1083; (b)
B. V. Subba Reddy, K. Ramesh, A. V. Ganesh,
G. G. K. S. Narayana Kumar, J. S. Yadav and R. Gree,
Tetrahedron Lett., 2011, 52, 495; (c) G. Sabitha,
M. Bhikshapathi, S. Nayak and J. S. Yadav, Synth.
Commun., 2011, 41, 8; (d) N. P. Selvam and P. T. Perumal,
Can. J. Chem., 2009, 87, 698–705.
15 (a) K. S. Atwal, G. J. Grover, F. N. Ferrara, S. Z. Ahmed,
P. G. Sleph, S. Dzwonczyk and D. E. Normandin, J. Med.
Chem., 1995, 38, 1996; (b) K. S. Atwal, G. J. Grover,
S. Z. Ahmed, F. N. Ferrara, T. W. Harper, K. S. Kim, 17 (a) J. S. Yadav, B. V. Subba Reddy, A. V. Ganesh and
P. G. Sleph, S. Dzwonczyk, A. D. Russell, S. Moreland,
J. R. McCullough and D. E. Normandin, J. Med. Chem.,
1993, 36, 3971.
G. G. K. S. Narayan Kumar, Tetrahedron Lett., 2010, 51,
2963; (b) G. Baishya, B. Sarmah and N. Hazarika, Synlett,
2013, 24, 1137.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 22387–22397 | 22397