Acid promoted cyclodehydration of amino alcohols with amide acetal

Article abstract of DOI:10.1039/c4ra10625c

A convenient acid-promoted cyclization protocol for the formation of azaheterocycles from amino alcohols is described. The reaction involves the use of N,N-dimethylacetamide dimethyl acetal (DMADA) as the activating reagent of the hydroxyl group. Using this protocol, pyrrolidines or piperidines with various substituents can be synthesized in good to high yields.

Full text of DOI:10.1039/c4ra10625c

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Acid promoted cyclodehydration of amino alcohols
with amide acetal†
Cite this: RSC Adv., 2014, 4, 60017
*
Soonho Hwang, Heemin Park, Yongseok Kwon and Sanghee Kim
Received 17th September 2014
Accepted 6th November 2014
A convenient acid-promoted cyclization protocol for the formation of azaheterocycles from amino
alcohols is described. The reaction involves the use of N,N-dimethylacetamide dimethyl acetal (DMADA)
as the activating reagent of the hydroxyl group. Using this protocol, pyrrolidines or piperidines with
various substituents can be synthesized in good to high yields.
DOI: 10.1039/c4ra10625c
www.rsc.org/advances
received much attention in substitution reactions,9,10 especially
when an amine is used as the nucleophile.
Introduction
As shown in Scheme 1, our cyclization strategy was based on
the formation of an acetal intermediate A from amino alcohol 1
via trans-acetalization and the in situ generation of carbenium
ion B for the activation of the hydroxyl group. Subsequent
intramolecular displacement of the activated hydroxyl group by
the amine nucleophile was envisioned to afford the azahetero-
cycle 2. For the successful implementation of our strategy, there
are several issues to be addressed. The rst is the complication
associated with the trans-acetalization of the reagent with the
hydroxyl group in the presence of the amino function. Despite
the improbability of the chemoselective trans-acetalization, we
The formation of saturated azaheterocycles, such as pyrrolidine
and piperidine, is of fundamental importance in organic
synthesis, not only for the obvious reason that they are ubiq-
uitous in nature,1 but also because they are key functional
motifs in numerous synthetic molecules.2 As a result, there is an
ever-growing number of synthetic methods, and the develop-
ment of effective and environmentally benign methods is of
considerable interest.3
The intramolecular displacement of a hydroxyl group by an
amine nucleophile is the most popular strategy to construct
azaheterocycles.3 In this type of cyclization, the hydroxyl group
requires prior activation for a smooth and high-yielding
process. Conventionally, the hydroxyl group has been acti-
vated by converting it to a good leaving group such as a halide or
sulfonate ester, which subsequently undergoes intramolecular
N-alkylation under basic conditions. To reduce the number of
chemical steps, direct methods were also devised, such as
phosphorus assisted Mitsunobu-type reactions and Appel
halogenation/in situ base-induced ring closure.4–6 However,
there are some drawbacks such as the use of toxic reagents and
the difficulty of byproduct removal. The direct ring closure of
amino alcohols can also be achieved under acidic conditions.7
However, vigorous conditions such as strong acid and high
temperature are needed to realize this type of transformation.
In our studies on the synthesis of azaheterocycle natural
products and their analogues, we were confronted with the
necessity to induce the cyclization of amino alcohols in neutral
or mildly acidic conditions. To this end, we focused our atten-
tion to an oxocarbenium ion for the activation of the hydroxyl
group. Although the chemistry of such carbenium ion has been
well explored,8 its use as an activator of a hydroxyl group has not
College of Pharmacy, Seoul National University, Seoul 151-742, Korea. E-mail:
pennkim@snu.ac.kr; Fax: +82-2-888-0649; Tel: +82-2-880-2487
† Electronic supplementary information (ESI) available: Copies of NMR spectra of
all new compounds, 1H NMR spectroscopy study, and stereochemical proofs. See
DOI: 10.1039/c4ra10625c
Scheme 1 Strategy for the synthesis of azaheterocycles.
RSC Adv., 2014, 4, 60017–60024 | 60017
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were optimistic about the success of our cyclization strategy
because the trans-acetalization is a process of thermodynamic
equilibrium. Even in the case that only small proportion of A is
formed compared to the N-acetalized intermediate C, the
equilibrium would shi to make more A if that small amount
undergoes an irreversible intramolecular cyclization readily.
Another important issue is the ambident electrophilic reactivity
of carbenium ion B. Although the preferred reactive site of such
carbenium species is dependent on the reaction conditions and
the nature of the nucleophile,8d we anticipated on the basis of
entropic considerations that the carbenium function in B would
react with the pendant amino group preferentially at the posi-
tion of the sp3 carbon (path a) over the sp2 oxocarbenium
carbon (path b) to yield azaheterocycles 2. Even in the case
where D is formed as an initial reaction product due to the
higher electrophilic reactivity of the sp2 oxocarbenium carbon,
the azaheterocycle products 2 could be eventually formed
through the reversible thermodynamic equilibrium processes.
Results and discussion
The simple amino alcohol 1a (Table 1) was chosen as the model
substrate to test the viability of the envisioned cyclization
process. At rst, several types of carbenium ion precursors (2
equiv.) were screened in the presence of catalytic amount of HCl
(0.1 equiv.)11 at the reux temperature of 1,2-dichloroethane
(1,2-DCE). When orthoesters were employed, such as trimethyl
orthoacetate (TMOA) and trimethyl orthobenzoate (TMOB), the
desired cyclized product was obtained, but only in low yield
(entries 1 and 2). Substantial amounts of the N-acyl derivative
and N,O-diacyl derivative of 1a were also formed.12 Alterations in
Scheme 2 Plausible reaction mechanism.
Table 2 Cyclization of substrate 1a with Vilsmeier reagenta
Table 1 Optimization of reaction conditions for the cyclization of
substrate 1aa
Yieldb (%)
Temp (ꢀC) Time (h) 2a
Entry Additive (eq) Solvent
5
1
2
3
4
5
6
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
rt
rt
rt
rt
rt
20
20
20
20
20
20
20
25
22
43
42
75
42
43
47
0
0
0
HCl (1.0)
SnCl4 (0.1)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Entry Reagentb Acid
Solvent Temp (ꢀC) Time (h) Yieldc (%)
1,2-DCE Reux
a
Reaction conditions: 1a (0.50 mmol), Vilsmeier reagent (1.0 mmol),
1
2
3
4
5
6
7
8
9
10
TMOA
TMOB
DMFDA HCl
DMADA HCl
DMADA HCld
DMADA SnCl4
HCl
HCl
1,2-DCE Reux
1,2-DCE Reux
1,2-DCE Reux
1,2-DCE Reux
CH2Cl2 rt
18
18
18
18
1
35
38
65
85
93
91
b
additive, solvent (10 mL) under N2. Isolated yield of the HCl salt
form of amine 2a and the amide 5.
CH2Cl2 rt
1
DMADA BF3$Et2O CH2Cl2 rt
18
18
18
18
65 (12)e
75 (8)e
75 (12)e
60 (23)e
the equivalent of reagents and acid, solvent, reaction time, and
temperature failed to suppress the production of the N-acylated
by-products.
However, when amide acetals13 were employed, the reaction
afforded the desired product without noticeable formation of
the N-acylated compounds. N,N-Dimethylacetamide dimethyl
acetal (DMADA)14 was much more efficient than N,N-dimethyl
formamide dimethyl acetal (DMFDA) in promoting the reaction
DMADA TiCl4
DMADA InBr3
DMADA CSA
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
a
Reaction conditions: 1a (0.50 mmol), reagent (1.0 mmol), acid (0.050
b
mmol), solvent (10 mL) under N2. Reagent for carbenium ion
precursor. Isolated yield of the HCl salt form of amine 2a. 1 equiv.
of HCl was used. The values in parentheses indicate the yield of
recovered starting material. CSA: (ꢁ)-camphorsulfonic acid.
60018 | RSC Adv., 2014, 4, 60017–60024
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d
e
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Table 3 Results of cyclization of amino alcohols 1a
(entries 3 vs. 4). The use of DMADA led to 2a in 18 h in 85% yield
under the screening conditions (0.1 equiv. of HCl, 1,2-DCE,
reux). The reaction with DMADA could proceed at room
temperature with very satisfactory results, but it required more
acid to go to completion (entry 5). A range of acids were
screened at room temperature to further optimize this reaction
and the typical results are shown in Table 1 (entries 6–10). SnCl4
was identied as the optimal choice for both chemical yield and
reaction time. A catalytic amount of SnCl4 (0.1 equiv.) provided
the product 2a aer 1 h at room temperature in 91% yield. Many
other Lewis acids produced the desired 2a, but did not fully
complete the reaction at room temperature in spite of a long
reaction time.
Entry
1
R1
R2
n
Time (h)
2
Yieldb (%)
1
2
3
4
1b
1c
1d
1e
4-OMe–Bn
4-CF3–Bn
Allyl
H
H
H
H
1
1
1
1
1
1
1
1
2b
2c
2d
2e
92
90
90
92
C7H15
5
1f
H
1
1
2f
91
To verify the mechanism that we have postulated, an NMR
study on the reaction of 1a with DMADA in CD2Cl2 was carried
out.15 In the presence of catalytic amounts of SnCl4 (ref. 16) at
room temperature, the 1H NMR spectrum revealed no
predominant intermediate (Fig. S1, ESI†). The cyclized product
2a and N,N-dimethylacetamide (DMA) were generated in a
nearly stoichiometric ratio.17 When the reaction mixture was
quenched with water during the course of the reaction, we could
detect the formation of the O-acetyl and N-acetyl derivatives, 3
and 4, in the same mutual ratio (Fig. S2, ESI†). These acetylated
derivatives might arise by the action of water on the proposed
carbenium intermediates (Scheme 2). This result together with
the detection of DMA as a byproduct strongly suggested that the
reaction proceeded via the envisaged intermediate carbenium
ion species, such as I, and intramolecular nucleophilic attack of
the amine.
6
1g
1
2g
93
c
7
8
9
10
11
12
13d
14d
1h
1i
1j
1k
1l
1m Bn
H
Bn
4-OMe–Bn
C7H15
Bn
H
H
H
H
1
2
2
2
3
1
1
1
16
2
2
2
16
5
2h
2i
2j
2k
2l
2m 89
—
90
91
89
c
H
—
Me
n-Bu
Ph
1n
1o
Bn
Bn
16
16
2n
2o
82
82
a
Reaction conditions: 1 (0.50 mmol), DMADA (1.0 mmol), SnCl4 (0.050
b
mmol), CH2Cl2 (10 mL), rt. Isolated yield of the HCl salt form of 2.
c
d
Cyclized product was not detected. The reaction was conducted in
˚
1,2-DCE (5 mL) at reux temperature with 100 wt% of 4 A molecular
sieve.
A carbenium ion intermediate similar to I has been proposed
in the activation of the hydroxyl group with Vilsmeier reagent.10
Although several functional groups, such as thiols and imides,
can serve as the nucleophile in the Vilsmeier reagent-mediated
displacement of hydroxyl groups, an amine group has not been
employed. We attempted the cyclization of 1a with Vilsmeier
reagent to verify the benet of DMADA (Table 2). When the
reaction was performed at room temperature in the absence or
presence of acid, the N-formyl chlorinated compound 5 was the
major product of the reaction (entries 1–3). In the presence of
base,18 the N-formyl chlorinated compound 5 was not formed.
The cyclized compound 2a was the major component, but the
yield was only 43% (entry 4). The reaction in THF afforded
similar result (entry 5). At the reux temperature of 1,2-DCE for
20 h, the yield of 2a increased up to 75% (entry 6), but ca. 20% of
by-products were still formed such as O-formylated and N,O-
diformylated derivatives of 1a. These results showed that the
cyclization of amino alcohol with Vilsmieier reagent was much
less efficient than that with DMADA with respect to reaction
conditions and yield.
Table 4 Results of cyclization of amino alcohol salts 1-HAa
Entry
1-HA
Time (h)
2-HA
Yieldb (%)
1
2
3
4
5
6
7
8
1a-HCl
1a-TFA
1b-HCl
1b-TFA
1c-HCl
1d-HCl
1i-HCl
1i-TFA
1j-HCl
1k-HCl
1m-HCl
1n-HCl
1
1
1
1
1
1
16
2
2
2a-HCl
2a-TFA
2b-HCl
2b-TFA
2c-HCl
2d-HCl
2i-HCl
2i-TFA
2j-HCl
2k-HCl
2m-HCl
2n-HCl
93
94
91
90
94
93
94
91
91
90
89
85
With the optimized reaction conditions (DMADA and
SnCl4), the cyclization of various types of substrates was
investigated (Table 3). The cyclization reaction proceeded
efficiently with various secondary amine substrates 1b–g to
provide the N-substituted pyrrolidines 2b–g (entries 1–6). The
reaction tolerated a broad range of N-substituted groups
including alkyl, allyl, benzyl, and even sterically bulky groups.
On the other hand, the reaction with the primary amine
9
10
11c
12c
2
16
5
a
Reaction conditions: 1-HA (0.50 mmol), DMADA (1.0 mmol), CH2Cl2
b
c
(10 mL), rt. Isolated yield of 2-HA. The reaction was conducted in
1,2-DCE (5 mL) at reux temperature with 100 wt% of 4 A molecular
˚
sieve.
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substrate 1h failed to yield the corresponding product and a
complex mixture of unidentied products was obtained (entry
7). This failure is most likely because of the facile condensa-
tion of the primary amine with DMADA to give the acet-
amidine or imidate ester.19
Under these reaction conditions, the six-membered
piperidine ring formation could also be achieved with high
yields (entries 8–10). However, the formation of a seven-
membered azepane ring was not successful even when
exposed to prolonged high temperature (entry 11). The
substrates with a secondary hydroxyl group were also well
suited for the reaction and gave the corresponding cyclized
products (entries 12–14). However, this type of substrates
Conclusions
In conclusion, we have developed a convenient and efficient
synthetic method for the generation of azaheterocycles from
amino alcohols. Our method is unique among other previously
developed synthetic methods in that the cyclization is promoted
by acid under mild conditions. This method is applicable to
substrates with various functional groups, especially those with
base-sensitive groups. A key feature of this protocol is the use of
an aza-oxo-stabilized carbenium ion for the activation of the
hydroxyl group which has rarely been explored in substitution
reactions, especially when an amine used as the nucleophile.
Several types of pyrrolidines and piperidines were successfully
prepared in good to high yields from the amino alcohols with
DMADA in the presence of an acid catalyst. Moreover, we found
that the acid salt of the amino alcohol could undergo the facile
reaction with DMADA without requiring any additional acid
catalyst. These results open avenues for the mild synthesis of
azaheterocycles with the advantages of simple manipulations,
especially when the amino alcohol substrate is in its salt form.
generally required
a longer reaction time and higher
temperature to reach completion. We considered this reac-
tion proceeds via SN2 mechanism because the chiral non-
racemic 1o afforded the corresponding cyclized product
without any racemization.15
Because the cyclized product could be obtained even with a
stoichiometric equivalent of HCl (Table 1, entry 5), we antici-
pated that the acid salt of the amino alcohol itself could
undergo the reaction with DMADA without needing the extra
acid catalyst. The success of such transformation would open
avenues for simple manipulation of the amino alcohol salt
substrates because it does not require the addition of base to
liberate the free amine function. As we expected, when the HCl
or TFA salt form of amino alcohol 1 was employed as a substrate
and merely treated with DMADA, the cyclized product 2 was
successfully obtained in high yields (Table 4).
Experimental
General information
All chemicals were of reagent grade and used as received. All
reactions were performed under dry nitrogen using distilled,
dry solvents. The reactions were monitored by TLC (Merck®,
Silica gel 60 F254). Flash column chromatography was per-
1
formed on silica gel (230–400 mesh). H (300 or 400 MHz) and
13C NMR (75 or 100 MHz) spectra were recorded. Chemical
shis (d) are reported in ppm relative to the non-deuteriated
solvent as internal reference; coupling constants (J) are given
in Hz. Multiplicities are denoted as follows: s ¼ singlet, d ¼
Building on the above results, an efficient process for con-
verting N-Boc protected amino alcohols to the corresponding
azaheterocycles was developed. For this, we employed the
known N-Boc protected amino alcohol 6 (Scheme 3) which has
been converted to the natural product crispine A (7) in several
ways.20
As the rst step, the Boc group was removed by using HCl in
CH2Cl2, and the hydrochloride salt 8 was obtained by evapora-
tion. Without further purication, salt 8 was next treated with
DMADA at room temperature for 1 h. This reaction sequence
gave a high yield of the cyclization product, crispine A (7), which
gave spectral data that was identical to what previously
reported.20,21
1
doublet, t ¼ triplet, q ¼ quartet, and m ¼ multiplet. The H
NMR spectra are presented as follows: chemical shi (multi-
plicity, coupling constant, integration). IR spectra were recor-
ded with a Fourier transform infrared spectrometer. High
resolution mass spectra (HRMS) were obtained by electron
ionization (EI) using a double focusing mass spectrometer.
Previously reported compounds were conrmed by comparison
of their 1H NMR with those of references.
Representative procedure for the synthesis of amino alcohol
1a (reductive amination protocol)
Benzaldehyde (6.9 mL, 67.3 mmol, 1.2 equiv.) and sodium
sulfate (Na2SO4, 15 g, 1.9 equiv.) were added to a solution of
commercially available 4-amino-1-butanol (5.0 g, 56.1 mmol, 1
equiv.) in CH2Cl2 (56 mL, 1.0 M) under N2 atmosphere. Aer
stirring for 15 h at room temperature, the crude reaction
mixture was ltered through a pad of Celite, and the ltrate was
concentrated under reduced pressure. The crude mixture
obtained was dissolved in EtOH (112 mL, 0.5 M) and NaBH4 (4.3
ꢀ
g, 112.2 mmol, 2 equiv.) was added portion wise at 0 C. Aer
stirring for an additional 2 h at room temperature, the reaction
was quenched by the addition of saturated NH4Cl solution at
0 ꢀC. Aer evaporation of the excess EtOH, the reaction mixture
Scheme 3 Synthesis of crispine A (7).
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was diluted with water and extracted twice with EtOAc. The 3717, 2933, 2858, 1651 (cmꢂ1); HRMS (EI) calcd C12H17F3NO
combined organic layers were washed with brine, dried over 248.1262 ([M + H]+), found 248.1269.
MgSO4, and concentrated in vacuo. The residue was puried by
ash chromatography on silica gel (CH2Cl2–MeOH, 10 : 1 + 1% NMR (400 MHz, CDCl3) d 0.77 (t, J ¼ 6.8 Hz, 3H), 1.18 (brs, 8H),
4-(Heptylamino)butan-1-ol (1e). Brown oil (1.5 g, 70%); 1H
NH4OH) to give known N-Bn amino alcohol 1a.22
1.40 (t, J ¼ 6.8 Hz, 2H), 1.54 (brs, 4H), 2.50 (t, J ¼ 7.3 Hz, 2H),
Amino alcohols 1b,23 1c, 1e, 1i,22 1j, 1k,24 and 1l22 were 2.55 (t, J ¼ 3.0 Hz, 2H), 3.46 (t, J ¼ 4.7 Hz, 2H), 3.90 (brs, 1H); 13
C
prepared by this reductive amination protocol with 11.2 mmol NMR (100 MHz, CDCl3): d ¼ 13.9, 22.4, 27.1, 28.2, 29.0, 29.3,
of corresponding amines. The following requisite aldehydes (p- 31.6, 32.1, 49.3, 49.4, 62.1; IR (CHCl3) nmax 3273, 2924, 2854,
anisaldehyde, 4-(triuoromethyl)benzaldehyde, and heptalde- 1462 (cmꢂ1); HRMS (EI) calcd C11H26NO 188.2014 ([M + H]+),
hyde) and amines (4-amino-1-butanol, 5-amino-1-pentanol and found 188.2017.
6-amino-1-hexanol) were commercially available.
4-((Bis(4-methoxyphenyl)methyl)amino)butan-1-ol
(1f).
1
Colorless oil (0.94 g, 75%); H NMR (400 MHz, CDCl3): d 1.58–
1.62 (m, 4H), 2.56 (t, J ¼ 5.5 Hz, 2H), 3.57–3.61 (m, 2H), 3.73 (s,
6H), 4.71 (brs, 1H), 6.81 (d, J ¼ 8.5 Hz, 4H), 7.24 (d, J ¼ 8.2 Hz,
4H); 13C NMR (100 MHz, CDCl3): d ¼ 28.3, 31.8, 48.0, 55.1 (2C),
62.6, 66.5, 113.9 (6C), 128.1 (4C), 135.7, 158.9; IR (CHCl3) nmax
3292, 2934, 2837, 1609 (cmꢂ1); HRMS (EI) calcd C19H26NO3
316.1913 ([M + H]+), found 316.1916.
Representative procedure for the synthesis of amino alcohol
1d (amidation – LAH reduction protocol)
Allylamine (2.3 mL, 30 mmol, 1.5 equiv.) and g-butyrolactone
(1.6 mL, 20 mmol, 1 equiv.) were dissolved in benzene (10 mL,
2.0 M) and reuxed for 12 h under a N2 atmosphere. Aer
cooling to room temperature, excess allylamine and benzene
were removed under reduced pressure. The residue was diluted
with EtOAc, washed with a 1.0 M HCl solution and brine, dried
over MgSO4, and concentrated in vacuo to give N-allyl-4-
hydroxybutanamide, which was used in the next step without
further purication. To a solution of LiAlH4 (1.5 g, 40 mmol, 2
equiv.) in THF (80 mL) at 0 ꢀC was added slowly dropwise a THF
(20 mL) solution of the amide (2.86 g, 20 mmol, 1 equiv.). Aer
stirring for 30 min at room temperature, the reaction mixture
was reuxed for 18 h. Aer cooling to 0 ꢀC, the reaction was
quenched by the careful addition of H2O (1.5 mL), 10% NaOH
solution (1.5 mL), and H2O (4.5 mL) sequentially. Aer stirring
an additional 2 h at room temperature, the crude mixture was
ltered through a pad of Celite, and the ltrate was concen-
trated under reduced pressure. The residue was puried by
ash chromatography on silica gel (CH2Cl2–MeOH, 10 : 1 + 1%
NH4OH) to give known N-allyl amino alcohol 1d.22
4-(Benzylamino)-3-phenylbutan-1-ol (1g). Pale yellow oil
1
(0.71 g, 70%); H NMR (400 MHz, CDCl3): d 1.81–1.95 (m, 2H),
2.79–2.85 (m, 2H), 2.88–2.90 (m, 1H), 3.50–3.56 (m, 1H), 3.62–
3.67 (m, 3H), 3.80 (s, 2H), 7.14 (d, J ¼ 7.4 Hz, 2H), 7.18–7.31 (m,
8H); 13C NMR (100 MHz, CDCl3): d ¼ 39.3, 44.8, 53.6, 55.1, 61.1,
126.5, 127.1 (2C), 127.2, 128.2 (2C), 128.5 (2C), 128.6 (2C), 138.7,
144.3; IR (CHCl3) nmax 3300, 2928, 2937, 1453 (cmꢂ1); HRMS (EI)
calcd C17H21NO 256.1701 ([M + H]+), found 256.1704.
5-((4-Methoxybenzyl)amino)pentan-1-ol (1j). Yellow oil (1.8
g, 73%); 1H NMR (400 MHz, CDCl3): d 1.31–1.35 (m, 2H), 1.44–
1.52 (m, 4H), 2.45 (brs, 2H), 2.56 (t, J ¼ 7.0 Hz, 2H), 3.52 (t, J ¼
6.4 Hz, 2H), 3.73 (s, 3H), 6.80 (d, J ¼ 8.3 Hz, 2H), 7.17 (d, J ¼ 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3): d ¼ 23.3, 29.4, 32.3, 48.9,
53.2, 55.1, 62.0, 113.6 (2C), 129.2 (2C), 132.0, 158.5; IR (CHCl3)
nmax 3296, 2932, 2857, 2837 (cmꢂ1); HRMS (EI) calcd C13H22NO2
224.1651 ([M + H]+), found 224.1657.
1
1-(Benzylamino)octan-4-ol (1n). Yellow oil (0.68 g, 72%); H
Amino alcohols 1f, 1g, 1m,25 1n, and 1o26 were prepared by
this amidation – LAH reduction protocol with 4 mmol of cor-
responding lactones. The following requisite lactones (g-valer-
olactone, g-octanolactone, and g-phenyl-g-butyrolactone) and
amines (4,40-dimethoxybenzhydrylamine and benzylamine)
were commercially available. a-Phenyl-g-butyrolactone required
for 1g was prepared by a previously developed procedure.27
NMR (400 MHz, CDCl3): d 0.87 (t, J ¼ 6.1 Hz, 3H), 1.18–1.55 (m,
10H), 1.60–1.73 (m, 2H), 2.52–2.58 (m, 1H), 2.72–2.77 (m, 1H),
3.48 (brs, 1H), 3.60 (m, 1H), 3.73 (s, 2H), 7.20–7.31 (m, 5H); 13
C
NMR (100 MHz, CDCl3): d ¼ 14.0, 22.8, 27.1, 28.1, 36.7, 37.3,
49.3, 53.8, 71.3, 127.1, 128.2 (2C), 128.4 (2C), 139.3; IR (CHCl3)
nmax 3290, 2923, 2858, 1453 (cmꢂ1); HRMS (EI) calcd C15H26NO
236.2014 ([M + H]+), found 236.2012.
Non racemic 4-(benzylamino)-1-phenylbutan-1-ol (1o). To a
stirred solution of known N-benzyl-4-oxo-4-phenylbutanamide28
(400 mg, 1.50 mmol, 1 equiv.) in CH2Cl2 was added formic acid–
Representative procedure for the preparation of amino
alcohol salts 1-HCl
HCl solution (4.0 M soln in dioxane, 5 equiv.) was slowly added triethylamine (5 : 2, 0.80 mL, molar ratio) and Noyori's transfer
to a solution of the obtained amino alcohol 1 (1 equiv.) in THF hydrogenation catalyst RuCl(p-cymene)[(S,S)-Ts-DPEN] (10 mg,
(0.3 M) at 0 ꢀC. Aer stirring for an additional 5 min, the crude 1 mol %) at room temperature. The resulting solution was
reaction mixture was concentrated under reduced pressure. The stirred at room temperature for 24 h. The reaction mixture was
crude solid was puried by recrystallization (EtOAc and hexane) diluted with water and extracted twice with EtOAc. The
to afford pure 1-HCl.
combined organic layers were washed with brine, dried over
4-((4-(Triuoromethyl)benzyl)amino)butan-1-ol (1c). Yellow MgSO4, and concentrated in vacuo. The residue was puried by
oil (2.1 g, 77%); 1H NMR (400 MHz, CDCl3) d 1.57 (brs, 4H), 2.61 ash chromatography on silica gel (hexane–EtOAc, 1 : 1) to give
(brs, 2H), 3.51 (brs, 2H), 3.76 (s, 2H), 7.36 (d, J ¼ 5.9 Hz, 2H), N-Bn amide alcohol as white solid (330 mg, 82%). 1H NMR (300
7.50 (d, J ¼ 5.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d ¼ 27.8, MHz, CDCl3) d 1.97–2.16 (m, 2H), 2.37 (t, J ¼ 7.1 Hz, 2H), 3.48
31.6, 49.1, 53.1, 62.2, 124.1 (q, J ¼ 270.3 Hz), 125.3 (q, J ¼ 3.7 Hz, (brs, 1H), 4.42 (d, J ¼ 5.5 Hz, 2H), 4.77 (dd, J ¼ 7.5 Hz, 4.6 Hz,
2C), 128.4 (2C), 129.3 (q, J ¼ 32.0 Hz), 143.3; IR (CHCl3) nmax
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1H), 6.12 (brs, 1H), 7.21–7.35 (m, 10H). The 1H NMR spectrum 60.1, 124.3 (q, J ¼ 270.2 Hz), 125.1 (q, J ¼ 3.7 Hz, 2C), 128.9 (2C),
was identical with that reported for its racemate.29
129.1 (q, J ¼ 32.1 Hz), 143.7; IR (CHCl3) nmax 2966, 2787, 1326,
To a solution of LiAlH4 (125 mg, 3.3 mmol, 3 equiv.) in THF 1124 (cmꢂ1); HRMS (EI) calcd C12H15F3N 230.1157 ([M + H]+),
ꢀ
(20 mL) at 0 C was added slowly dropwise a THF (5 mL) solu- found 230.1153.
tion of the N-Bn amide alcohol (296 mg, 1.1 mmol, 1 equiv.).
1-Allylpyrrolidine (2d).33 Colorless oil (49.4 mg, 90%); 1H
Aer stirring for 30 min at room temperature, the reaction NMR (400 MHz, CDCl3) d 1.79 (brs, 4H), 2.54 (brs, 4H), 3.12 (d, J
mixture was reuxed for 18 h. Aer cooling to 0 ꢀC, the reaction ¼ 6.4 Hz, 2H), 5.09 (d, J ¼ 10.0 Hz, 2H), 5.19 (d, J ¼ 17.1 Hz, 2H),
was quenched by the careful addition of H2O (125 mL), 10% 5.88–5.98 (m, 1H).
NaOH solution (125 mL), and H2O (375 mL) sequentially. Aer
1
1-Heptylpyrrolidine (2e).34 Colorless oil (77.3 mg, 92%); H
stirring an additional 2 h at room temperature, the crude NMR (400 MHz, CDCl3) d 0.85 (t, J ¼ 6.4 Hz, 3H), 1.26 (brs, 8H),
mixture was ltered through a pad of Celite, and the ltrate was 1.50 (t, J ¼ 6.8 Hz, 2H), 1.76 (brs, 4H), 2.41 (t, J ¼ 7.8 Hz, 2H),
concentrated under reduced pressure. The residue was puried 2.50 (brs, 4H).
by ash chromatography on silica gel (CH2Cl2–MeOH, 10 : 1 +
1-(Bis(4-methoxyphenyl)methyl)pyrrolidine (2f).35 Colorless
1
1% NH4OH) to give non-racemic amino alcohol 1o as white solid (135.4 mg, 92%); H NMR (400 MHz, DMSO) d 1.68 (brs,
solid (265 mg, 85%). 1H NMR (300 MHz, CDCl3) d 1.56–1.74 (m, 4H), 2.30 (brs, 4H), 3.68 (s, 6H), 4.09 (brs, 1H), 6.81 (d, J ¼ 8.0
2H), 1.76–1.87 (m, 1H), 1.89–1.99 (m, 1H), 2.66 (qd, J ¼ 4.1 Hz, Hz, 4H), 7.31 (d, J ¼ 7.8 Hz, 4H).
12.0 Hz, 1H), 2.81 (qd, J ¼ 3.8 Hz, 11.6 Hz, 1H), 3.80 (s, 2H), 4.68
1-Benzyl-3-phenylpyrrolidine (2g).36 Brown oil (111.3 mg,
1
(dd, J ¼ 3.1 Hz, 8.2 Hz, 1H), 7.14–7.37 (m, 10H). The H NMR 93%); 1H NMR (300 MHz, CDCl3) d 1.81–1.92 (m, 1H), 2.25–2.37
spectrum was identical with that reported for its racemate.26 (m, 1H), 2.48 (t, J ¼ 8.5 Hz, 1H), 2.63–2.71 (m, 1H), 2.78–2.86 (m,
The optical purity (91% ee) of non-racemic amino alcohol 1o 1H), 3.02 (t, J ¼ 8.5 Hz, 1H), 3.29–3.40 (m, 1H), 3.65 (s, 2H), 7.11–
was determined by 1H NMR spectroscopic analysis of N-Boc (S)- 7.17 (m, 1H), 7.21–7.35 (m, 9H).
(+)-a-(triuoromethyl)phenylacetyl ester derivative.
1-Benzylpiperidine (2i).31 Yellow oil (78.2 mg, 90%); 1H NMR
(400 MHz, CDCl3) d 1.40 (brs, 2H), 1.52–1.56 (m, 4H), 2.35 (brs,
4H), 3.45 (s, 2H), 7.21–7.29 (m, 5H).
Representative procedure for the SnCl4-catalyzed cyclization
of amino alcohols 1 (Table 2)
1-(4-Methoxybenzyl)piperidine (2j).31 Yellow oil (93.4 mg,
91%); 1H NMR (400 MHz, CDCl3) d 1.40 (brs, 2H), 1.51–1.57 (m,
4H), 2.33 (brs, 4H), 3.39 (s, 2H), 3.77 (s, 3H), 6.82 (d, J ¼ 8.2 Hz,
2H), 7.20 (d, J ¼ 8.2 Hz, 2H).
To a stirred solution of amino alcohol 1 (0.50 mmol, 1 equiv.) in
CH2Cl2 (0.05 M, 10 mL) was added SnCl4 (1.0 M soln in CH2Cl2,
50 mL, 0.050 mmol, 0.1 equiv.) and N,N-dimethylacetamide
dimethyl acetal (DMADA, 0.17 mL, 1.0 mmol, 2 equiv.) at room
temperature. Aer disappearance of the starting material, HCl
(4.0 M soln in dioxane, 0.50 mL, 2.0 mmol, 4 equiv.) was added
to make 2 into its corresponding salt. Aer stirring an addi-
tional 5 min at room temperature, the crude mixture was
azeotropically evaporated under reduced pressure. The residue
was puried by ash chromatography on silica gel (CH2Cl2–
MeOH, 10 : 1) to give 2-HCl.30 Aer checking the chemical yield,
small amounts of 2-HCl was basied with a NaOH solution to
conrm the chemical identity.
1-Heptylpiperidine (2k).37 Colorless oil (81.2 mg, 89%); 1H
NMR (400 MHz, CDCl3) d 0.85 (t, J ¼ 5.4 Hz, 3H), 1.24 (brs, 8H),
1.39–1.45 (m, 4H), 1.52–1.56 (m, 4H), 2.24–2.19 (m, 2H), 2.33
(brs, 4H).
1-Benzyl-2-methylpyrrolidine (2m).38 Yellow oil (78.5 mg,
89%); 1H NMR (300 MHz, CDCl3) d 1.15 (d, J ¼ 6.1 Hz, 3H), 1.37–
1.50 (m, 1H), 1.53–1.75 (m, 2H), 1.86–1.97 (m, 1H), 2.07 (q, J ¼
9.0 Hz, 1H), 2.31–2.42 (m, 1H), 2.84–2.91 (m, 1H), 3.11 (d, J ¼
12.7 Hz, 1H), 4.00 (d, J ¼ 13.0 Hz, 1H), 7.18–7.35 (m, 5H).
1-Benzyl-2-butylpyrrolidine (2n).39 Yellow oil (88.5 mg, 82%);
1H NMR (400 MHz, CDCl3) d 0.87 (t, J ¼ 6.1 Hz, 3H), 1.50–1.57
(m, 5H), 1.62–1.72 (m, 4H), 1.89–1.94 (m, 1H), 2.08–2.10 (m,
1H), 2.31 (brs, 1H), 2.90 (brs, 1H), 3.15 (d, J ¼ 8.1 Hz, 1H), 4.04
(d, J ¼ 9.6 Hz, 1H), 7.20–7.31 (m, 5H).
Representative procedure for the cyclization of amino alcohol
salts 1-HA (Table 3)
To a stirred solution of 1-HA (0.50 mmol, 1 equiv.) in CH2Cl2
1-Benzyl-2-phenylpyrrolidine (2o).40 Colorless oil (97.4 mg,
(0.05 M, 10 mL) was added DMADA (0.17 mL, 1.0 mmol, 2 82%); 1H NMR (300 MHz, CDCl3) d 1.66–1.72 (m, 2H), 1.75–1.85
equiv.) at room temperature. The following reaction procedure (m, 1H), 2.05–2.17 (m, 2H), 2.93–3.05 (m, 2H), 3.29 (t, J ¼ 7.9 Hz,
was the same as the above procedure.
2H), 3.78 (d, J ¼ 13.0 Hz, 1H), 7.10–7.30 (m, 8H), 7.40 (d, J ¼ 7.3
1
1-Benzylpyrrolidine (2a).31 Colorless oil (74.2 mg, 93%); H Hz, 2H). The optical purity of non-racemic 2o was determined
NMR (300 MHz, CDCl3) d 1.68–1.81 (m, 4H), 2.40–2.50 (m, 4H), by chiral HPLC analysis (Chiracel OJ; retention time, major
3.58 (s, 2H), 7.33–7.41 (m, 5H).
10.56 min, minor 15.92 min; 92% ee).
1-(4-Methoxybenzyl)pyrrolidine (2b).32 Yellow oil (87.1 mg,
92%); 1H NMR (300 MHz, CDCl3) d 1.74–1.85 (m, 4H), 2.53–2.58
(m, 4H), 3.57 (s, 2H), 3.79 (s, 3H), 6.82–6.87 (m, 2H), 7.24–7.27
(m, 2H).
Procedure for capturing O-acetyl derivative 3 and N-acetyl
derivative 4
1-(4-(Triuoromethyl)benzyl)pyrrolidine (2c). Colorless oil To a stirred solution of 1a (0.50 mmol, 1 equiv.) in CH2Cl2 (0.05
1
(103.4 mg, 90%); H NMR (400 MHz, CDCl3) d 1.77 (brs, 4H), M, 10 mL) was added SnCl4 (0.1 M soln in CH2Cl2, 50 mL, 0.0050
2.48 (brs, 4H), 3.64 (s, 2H), 7.40 (d, J ¼ 7.9 Hz, 2H), 7.54 (d, J ¼ mmol, 0.01 equiv.) and DMADA (0.17 mL, 1.0 mmol, 2 equiv.) at
7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 23.4 (2C), 54.2 (2C), room temperature and continued to stir for 30 min. Aer the
60022 | RSC Adv., 2014, 4, 60017–60024
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mixture was cooled to 0 ꢀC, the reaction was quenched with residue was puried by ash chromatography on silica gel
water and extracted with EtOAc. The organic layer was washed (CH2Cl2–MeOH, 20 : 1 + 1% NH4OH) to give crispine A (7) (93.2
1
with saturated NaHCO3 solution and brine, dried with MgSO4, mg, 80% for 2-steps) as a colorless solid. H NMR (300 MHz,
and concentrated in vacuo. The resulting residue was puried by CDCl3) d 1.63–1.76 (m, 1H), 1.81–1.99 (m, 2H), 2.25–2.35 (m,
ash chromatography on silica gel (CH2Cl2–MeOH, 15 : 1 + 1% 1H), 2.52–2.74 (m, 3H), 2.92–3.09 (m, 2H), 3.12–3.19 (m, 1H),
NH4OH) to give 3 and 4.
3.43 (t, J ¼ 8.2 Hz, 1H), 3.82 (s, 6H), 6.54 (s, 1H), 6.58 (s, 1H).
4-(Benzylamino)butyl acetate (3). Colorless oil (26.5 mg,
24%); 1H NMR (400 MHz, CD2Cl2) d 1.21–1.56 (m, 3H), 1.62–1.69
(m, 2H), 1.99 (s, 3H), 2.62 (t, J ¼ 6.9 Hz, 2H), 3.75 (s, 2H), 4.03 (t,
J ¼ 6.5 Hz, 2H), 7.19–7.23 (m, 1H), 7.27–7.30 (m, 4H); 13C NMR
(100 MHz, CD2Cl2) d 21.1, 26.9, 27.0, 49.3, 54.2, 64.7, 127.1,
128.4 (2C), 128.6 (2C), 141.3, 171.2; IR (CHCl3) nmax 3029, 2940,
2817, 1737 (cmꢂ1); HRMS (EI) calcd C13H19NO2 221.1451 ([M +
H]+), found 221.1448.
Acknowledgements
This work was supported by the Mid-Career Researcher
Program (no. 2013R1A2A1A01015998) of the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MSIP).
N-benzyl-N-(4-hydroxybutyl)acetamide (4).40 Colorless oil
(25.4 mg, 23%); 1H NMR (300 MHz, CDCl3) d 1.45–1.64 (m, 4H),
1.94 (brs, 1H), 2.09 (s, 3H, rotamer), 2.14 (s, 3H, rotamer), 3.21
(t, J ¼ 7.3 Hz, 2H, rotamer), 3.38 (t, J ¼ 6.9 Hz, 2H, rotamer),
3.59–3.65 (m, 2H), 4.51 (s, 2H, rotamer), 4.58 (s, 2H, rotamer),
7.13–7.37 (m, 5H).
Notes and references
1 (a) Modern Alkaloids. Structure, Isolation, Synthesis and
Biology, ed. E. Fattorusso and O. Taglialatela-Scafati, Wiley-
VCH Verlag, Weinheim, Germany, 2008; (b) D. O'Hagan,
Nat. Prod. Rep., 2000, 17, 435; (c) A. R. Pinder, Nat. Prod.
Rep., 1986, 3, 171.
2 C. W. Bird, in Comprehensive Heterocyclic Chemistry II, ed. A.
R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon,
Oxford, 1996, vol. 2, ch. 19, pp. 933–967.
3 For reviews, see: (a) N. R. Candeias, L. C. Branco,
P. M. P. Gois, C. A. M. Afonso and A. F. Trindade, Chem.
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Chem. Soc., Perkin Trans. 1, 2000, 17, 2862; (c)
M. G. P. Buffat, Tetrahedron, 2004, 60, 1701; (d)
P. M. Weintraub, J. S. Sabol, J. M. Kane and
D. R. Borcherding, Tetrahedron, 2003, 59, 2953; (e)
Representative procedure for the cyclization of amino alcohol
1a using Vilsmeier reagent (Table 2)
To a stirred solution of amino alcohol 1a (0.50 mmol, 1 equiv.)
in solvent (0.05 M, 10 mL) was added additive and Vilsmeier
reagent, easily prepared from dimethyl formamide and oxalyl
chloride,10b (1.0 mmol, 2 equiv.) at room temperature. The
reaction mixture was stirred at the indicated temperature for
the indicated amount of time. Aer disappearance of the
starting material, HCl (4.0 M soln in dioxane, 0.50 mL, 2.0
mmol, 4 equiv.) was added to make 2a into its corresponding
salt. Aer stirring an additional 5 min at room temperature, the
crude mixture was azeotropically evaporated under reduced
pressure. The residue was puried by ash chromatography on
silica gel (CH2Cl2–MeOH, 10 : 1) to give 2a-HCl and 5.
`
M. Pichon and B. Figadere, Tetrahedron: Asymmetry, 1996,
7, 927; (f) R. C. Larock, in Comprehensive Organic
Transformations, Wiley-VCH, New York, 2nd edn, 1999, pp.
689–702 and 779–784.
N-benzyl-N-(4-chlorobutyl)formamide (5). Yellow oil; 1H
NMR (400 MHz, CDCl3) d 1.57–1.80 (m, 4H), 3.14 (t, J ¼ 6.4 Hz,
1H), 3.23 (t, J ¼ 7.1 Hz, 1H), 3.44–3.50 (m, 2H), 4.37 (s, 2H,
rotamer), 4.52 (s, 2H, rotamer), 7.17–7.36 (m, 5H), 8.17 (s, 1H,
rotamer), 8.27 (s, 1H, rotamer); 13C NMR (100 MHz, CDCl3) d
24.1, 25.4, 29.2, 29.6, 40.9, 44.2, 44.4, 45.2, 46.1, 51.2, 127.5,
127.6, 128.1, 128.2, 128.7, 128.9, 135.9, 136.3, 162.7, 162.9; IR
(CHCl3) nmax 3032, 2932, 2868, 1669 (cmꢂ1); HRMS (EI) calcd
4 For a leading reference and some recent examples of
Mitsunobu-type cyclizations, see: (a) R. C. Bernotas and
R. V. Cube, Tetrahedron Lett., 1991, 32, 161; (b) H. Wong,
E. C. Garnier-Amblard and L. S. Liebeskind, J. Am. Chem.
Soc., 2011, 133, 7517; (c) N. Saha, T. Biswas and
S. K. Chattopadhyay, Org. Lett., 2011, 13, 5128; (d) Y. Ukaji,
M. Imai, T. Yamada and K. Inomata, Heterocycles, 2000, 52,
563.
5 For some recent examples of Appel-type cyclizations, see: (a)
G. Archibald, C.-P. Lin, P. Boyd, D. Barker and V. Caprio, J.
Org. Chem., 2012, 77, 7968; (b) J.-J. Zhuang, J.-L. Ye,
H.-K. Zhang and P.-Q. Huang, Tetrahedron, 2012, 68, 1750;
(c) H. Yoon, K. S. Cho and T. Sim, Tetrahedron: Asymmetry,
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C
12H16ClNO 225.0913 ([M + H]+), found 225.0911.
Crispine A (7).21 To a stirred solution of known N-Boc pro-
tected amino alcohol 620a (175.5 mg, 0.50 mmol, 1 equiv.) in
CH2Cl2 (0.1 M, 5.0 mL) was added HCl (4.0 M soln in dioxane,
1.0 mL) at 0 ꢀC under N2 atmosphere. Aer disappearance of the
starting material, excess HCl and solvent were azeotropically
evaporated under reduced pressure to give crude HCl salt 8. Salt
8 was dissolved in CH2Cl2 (0.05 M, 10 mL), and DMADA (0.17
mL, 1.0 mmol, 2 equiv.) was added at room temperature. Aer
allowing the reaction to proceed for 1 h, the reaction was
quenched with 1.0 M NaOH solution at 0 ꢀC and then the
mixture was extracted twice with EtOAc. The combined organic
layers were dried over MgSO4, and concentrated in vacuo. The
6 For other approaches for direct cyclization of amino
alcohols, see: (a) D. Pingen and D. Vogt, Catal. Sci.
Technol., 2014, 4, 47; (b) P. H. Huy and A. M. P. Koskinen,
Org. Lett., 2013, 15, 5178; (c) F. Xu, B. Simmons,
R. A. Reamer, E. Corley, J. Murry and D. Tschaen, J. Org.
¨
Chem., 2008, 73, 312; (d) R. M. de Figueiredo, R. Frohlich
and M. Christmann, J. Org. Chem., 2006, 71, 4147.
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