N-Arylazetidines: Preparation through Anionic Ring Closure

Article abstract of DOI:10.1021/acs.joc.6b00169

We report herein an efficient synthesis of diversely substituted N-aryl-2-cyanoazetidines based on an anionic ring-closure reaction. These compounds can be prepared from β-amino alcohols in enantiomerically pure form through a three-step sequence involving (i) copper-catalyzed N-arylation, (ii) N-cyanomethylation of the secondary aniline, and (iii) one-pot mesylation followed by ring closure induced by a base. This high-yielding sequence gives access to azetidines with a predictable and adjustable substitution pattern and also with predictable diastereoselectivity. These compounds are susceptible to multiple further derivatizations through Suzuki coupling or nitrile transformation, thus appearing as valuable new scaffolds for medicinal chemistry. Their rigid shape, featuring an almost planar N-arylamine and a planar four-membered ring, was revealed by both AM1 calculations and X-ray crystallography.

Full text of DOI:10.1021/acs.joc.6b00169

Article
pubs.acs.org/joc
N‑Arylazetidines: Preparation through Anionic Ring Closure
Pierre Quinodoz, Bruno Drouillat, Karen Wright, Jerome Marrot, and Franco̧ is Couty*
́
̂
Institut Lavoisier de Versailles, UMR 8180. Universite
Etats-Unis, Versailles 78035 Cedex, France
́ ́
de Versailles St-Quentin-en-Yvelines, Universite Paris Saclay, 45, Avenue des
S
* Supporting Information
ABSTRACT: We report herein an efficient synthesis of diversely substituted N-aryl-2-cyanoazetidines based on an anionic ring-
closure reaction. These compounds can be prepared from β-amino alcohols in enantiomerically pure form through a three-step
sequence involving (i) copper-catalyzed N-arylation, (ii) N-cyanomethylation of the secondary aniline, and (iii) one-pot
mesylation followed by ring closure induced by a base. This high-yielding sequence gives access to azetidines with a predictable
and adjustable substitution pattern and also with predictable diastereoselectivity. These compounds are susceptible to multiple
further derivatizations through Suzuki coupling or nitrile transformation, thus appearing as valuable new scaffolds for medicinal
chemistry. Their rigid shape, featuring an almost planar N-arylamine and a planar four-membered ring, was revealed by both
AM1 calculations and X-ray crystallography.
azetidines display a rigid shape, with an almost planar four-
membered ring and heterocyclic nitrogen atom, as demonstrated
by X-ray crystallography and AM1 calculations. This rigid shape
is a key point for the use of these platforms for the exploration of
chemical space in medicinal chemistry.
INTRODUCTION
■
Azetidines have emerged as privileged scaffolds in medicinal
chemistry within the past decade, which can be ascribed to patent
strategies based on novelty, promoted by the recent commercial
availability of azetidinyl building blocks,1 coupled with the
increasing number of methods for their preparation.2 Thus, in
this area, new rigid spiro-azetidinyl scaffolds for the exploration
of chemical space have been developed by Carreira’s group,3
while new methodologies based on organocatalysis have
appeared to prepare these heterocycles in optically enriched
form.4 At the same time, while these nitrogen heterocycles are
becoming very popular, the design and synthesis of more
complicated azetidinyl scaffolds with a predictable shape, taking
into account the key problem of absolute stereochemistry, and
fitted with functional groups allowing further functionalization
still remains a challenge. Such stereodefined scaffolds appear to
be ideal platforms for diversity-oriented synthesis (DOS), with
the aim to explore chemical space.5
This paper reports the synthesis of diversely substituted N-
aryl-2-cyanoazetidines 4 via a three-step sequence involving (i)
N-arylation of a β-amino alcohol 1, (ii) N-cyanomethylation of 2,
and (iii) a one-pot mesylation/intramolecular alkylation
promoted on the corresponding adduct 3 by a base (Scheme
1). The produced N-aryl-2 cyanoazetidines 4 offer high structural
diversity considering the large array of available precursors and
can be further derivatized through Pd-catalyzed coupling
reactions, if R′ = Br or R″ = 4-C6H4Br or through nitrile
transformations. We also demonstrate herein that these
The synthesis of the N-arylated azetidines6 described herein
relies on a key anionic ring-closure step, which had previously
been explored only with N-alkyl substrates.7 The adaptation of
this powerful, yet under-used, synthetic strategy to N-arylated
substrates was not straightforward because of fundamental
differences between tertiary amines and anilines, including lower
basicity and nucleophilicity and flattening of the nitrogen atom in
tertiary anilines compared to tertiary amines. This last point is a
crucial parameter for the key projected ring closure, since this
flattening would potentially increase the distance between the
reacting anion and the electrophilic carbon, thus rendering the 4-
exo-tet cyclization step more difficult.8
RESULTS AND DISCUSSION
■
The N-aryl β-amino alcohols required as substrates for the
synthesis of N-arylazetidines following Scheme 1 were prepared
by Cu-catalyzed N-arylation of the corresponding β-amino
alcohols. This coupling reaction is particularly efficient with β-
amino alcohols and does not require an additional ligand, as
shown by Buchwald.9 When the amino alcohol could not be used
Received: January 25, 2016
© XXXX American Chemical Society
A
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Scheme 1. Three-Step Synthesis of N-Aryl-2-cyanoazetidines through Anionic Ring Closure
Scheme 2. Structures and Yields of Prepared N-Arylamino Alcohols
Scheme 3. N-Alkylation with Bromoacetonitrile Gives Low Yields of N-Cyanomethylated Products
in excess for economic reasons, Buchwald’s procedure was used
(ArI, 5 mol % of CuI, NaOH 2 equiv in i-PrOH). Otherwise,
starting from ethanolamine 1 (R = H, 3 equiv), the reaction was
conducted without solvent (ArI, CuCl, 10 mol %, KOH, 2 equiv)
following Han’s procedure,10 with a limited addition of DMSO
(0.4 mL/mmol) in some cases to aid solubility. The structures
and yields of the prepared N-arylamino alcohols are shown in
Scheme 2.
The second step of the synthesis was N-cyanomethylation.
This step is usually carried out in the case of N-alkylamino
alcohols by alkylation with the required α-bromonitrile,11 but we
found that the lowered nucleophilicity of N-arylamines
considerably reduced the efficiency of this alkylation step, even
with unsubstituted 5. Thus, conventional heating (MeCN,
BrCH2CN, K2CO3, reflux) only gave trace amounts of 14 starting
from 5, and protracted reaction time or solvent change (DMF,
100 °C) only led to low isolated yields. After extensive
optimization, the best conditions were found to involve
microwave activation for 45 min at 110 °C in MeCN to afford
14 in a modest 44% yield. However, under these conditions, N-
naphthyl-substituted amino alcohol 8 led to 15 with an
unsatisfactory yield of 28% (Scheme 3).
Gratifyingly, a two-step procedure involving the formation of
an intermediate oxazolidine followed by acid-catalyzed opening
by cyanide anion proved much more efficient and allowed the
preparation of nonsubstituted amino nitriles 14−21 in high
yields. Alternatively, when an aryl aldehyde was used instead of
paraformaldehyde, the intermediate 2-aryloxazolidine was also
cleanly opened with HCN (KCN/AcOH) to give the substituted
amino nitrile 22. The conditions used for each substrate were
modulated in order to optimize yields, and the structures of the
products are shown in Table 1.
B
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Table 1. Cyanomethylation via an Oxazolidine
a
Method A: paraformaldehyde (2 equiv), MeCN, reflux, 12 h. Method B: 40% aqueous formaldehyde (1.2 equiv), CH2Cl2, 4 Å MS, rt, 12 h. Method
C: paraformaldehyde (2 equiv), azeotropic reflux, benzene, APTS cat. 12 h. Method D: 4-BrC6H4CHO (1 equiv), azeotropic reflux, benzene, APTS
b
cat. 12 h. Method 1: MeCN, TMSCN (2equiv), AcOH (2 equiv), reflux, 12 h. Method 2: AcOH, KCN (8 equiv), 70 °C, 1 h. Method 3: AcOH,
TMSCN (2 equiv), 70 °C, 1 h. Method 4: BF3·Et2O, TMSCN (2 equiv) rt, 15 min. For combination of methods A/1 and A/4, the reaction was
conducted in one pot. For other combinations, intermediate oxazolidine was isolated before the opening step.
C
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Scheme 4. Synthesis of N-Aryl-2-cyanoazetidines 25−30 via an Isolable Intermediate Mesylate
Scheme 5. Diastereoselectivity Issues in Anionic Ring-Closure Reactions
The crucial intramolecular alkylation step was studied next.
When N-alkyl substrates are used, activation of the alcohol is
usually carried out by chlorination (SOCl2) and involves
participation of the lone pair of the nitrogen atom to produce
an aziridinium ion, which results in a stereospecific chlorination
via a double SN2 process.11,12 It should be noted that with such
D
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nucleophilic amines activation of the alcohol as a mesylate
(MeSO2Cl, Et3N) also gives the corresponding chloride via the
same aziridinium intermediate and its opening by chloride
anion.13 Since the opening of the produced intermediate
aziridinium ion might not be regioselective, this activation can
lead to mixtures of chloride isomers.12 In the case of N-aryl
substrates, different behavior was observed since mesylation of
14 (MsCl, 1.2 equiv, Et3N, CH2Cl2, 0 °C) quantitatively gave the
corresponding mesylate 24, without any trace of the correspond-
ing chloride, and was found to be stable enough to be isolated.
This crude compound was then treated with t-BuOK (1.2 equiv
in THF), which gave a high overall yield of 2-cyanoazetidine 25.
This two-step procedure was next applied to alcohols 15−19 to
afford good yields of 2-cyanoazetidines 26−30 (Scheme 4).
With the ethyl-substituted amino alcohol 21, this procedure
gave a 6/4 epimeric mixture of azetidines 31a and 31b that could
be separated by preparative TLC and whose relative config-
urations were determined by NOESY experiments. Only the 4-
ethyl-substituted azetidine was produced, confirming that the
rearrangement of the carbon chain via an aziridinium ion did not
occur. However, when mesylation of 20 with a more reactive
secondary benzylic alcohol was performed, only the chloride 32
was produced (isolated as a 1:1 mixture together with starting
20). In this case, the previously mentioned participation of the
lone pair of the nitrogen aniline and formation of an intermediate
aziridinium ion took place, followed by exclusive ring-opening at
the benzylic position. When this mesylation was conducted in
THF instead of dichloromethane, the intermediate chloride was
not isolated and subsequent addition of t-BuOK at 0 °C (4 equiv)
smoothly generated an epimeric mixture of 33a and 33b in a 10/
90 ratio in good overall yield. This one-pot procedure was next
applied to 22 and 23, producing a mixture of epimeric azetidines
34a,b and azetidine 35 as shown in Scheme 5. The relative
configuration of the major epimers 33a and 34a was confirmed
by X-ray crystallography (Scheme 5).
AM1 calculations (B3LYP 6.31G + ) were performed in order
to evaluate the thermodynamic stabilities of the epimeric
mixtures of 2-cyanoazetidines 31a,b, 33−34a,b, and 37a,b
(Table 2; see the SI for details). The optimized structures
showed a slight preference for the cis compounds in the case of
2,4-disubstituted azetidines 31a,b and 34a,b. In the case of
norephedrine-derived azetidines 33a,b and phenylglycinol-
derived 37a,b, calculation predicts that the 2,3-trans compounds
33a and 37a would be more stable. The experimental
distribution of diastereoisomers fits quite well with those
calculated for 33a,b, 34a,b, and 37a,b, suggesting that
diastereoselectivity results in these cases from rapidly attained
thermodynamic control. However, in the case of 31a,b, the
calculated ratio does not correspond with the experimental
results, suggesting that the two-step procedure used to prepare
these compounds does not allow complete thermodynamic
equilibrium to be reached.
The structures of the optimized calculated structures (MP2
level) are shown in Figure 1 for 33a (right) and 34a (left).
Particularly noteworthy is the marked planarity of the four-
membered ring, which adopts a more pronounced envelope form
in the related N-alkylazetidines,11 and the flattening of the
heterocyclic nitrogen atom, with a deviation angle from planarity
of ca. 25° in 33a and 23° in 34a. These calculations suggest a
quite rigid structure with limited conformational exchange, and
these minimized structures fit very well with the X-ray data
obtained from both 33a and 34a (see the SI for ORTEP
figures),14 which show an average angle of deviation from
planarity of 32°.15
The reactivity of these compounds was evaluated through
several transformations. N-Alkylation of 25 with methyl
trifluoromethanesulfonate gave azetidinium ion 38 with
moderate diastereoselectivity. The latter could be opened by
an azide anion, yielding a mixture of 39 and 40. The nitrile
moiety in 25 reacted with butyllithium to give the corresponding
ketone 41 that could be reduced with high diastereoselectivity
(88% de) to afford the corresponding anti amino alcohol 42. The
structure of the major diastereoisomer in 42 was assigned on the
basis of a chelated model operating with similar N-
alkylazetidines.16 These experiments demonstrate that the N-
arylazetidines show a roughly similar reactivity profile as the N-
alkyl-2-cyanoazetidines. Additionally, Suzuki couplings were
evaluated with substrates 30 and 35, and phenyl coupling was
successfully achieved to give 43 and 44 (Scheme 7).
The position of the phenyl substituent in 34a,b could also be
modulated. When starting 22 was mesylated in MeCN and the
produced mesylate was heated for 12 h at reflux, the chloride 36
was isolated as a single isomer in good yield. This compound
results from regioselective ring-opening of the intermediate
aziridinium by the chloride anion at the benzylic position, a
rearrangement which spontaneously occurs without heating in
case of the more nucleophilic N-Bn substrates.11 Anionic ring
closure of this compound then gave epimeric 37a,b in a 73/27
ratio (Scheme 6). The relative configurations of these
1
CONCLUSIONS
compounds were assigned by comparison with the H NMR
■
spectra of 33a,b, as the H-2 signal in the 2,3-cis isomers appears
more deshielded (5.02 and 5.21 ppm) than in the 2,3-trans
isomers (4.38 and 4.56 ppm).
In conclusion, we have demonstrated that N-aryl-2-cyanoazeti-
dines can be prepared in good overall yields from β-amino
alcohols. Considering the large panel of commercially available β-
amino alcohols and aryl halides, coupled with the multiple
possible chemical transformations of the cyano moiety, this
simple procedure gives access to a vast array of azetidines fitted
with substituents displaying predictable spatial orientation. This
work further demonstrates that the synthetic route toward
azetidines based on anionic ring closure is particularly appealing.
Scheme 6. Regioselective Rearrangement by Heating of the
Mesylate Derived from 22
EXPERIMENTAL SECTION
■
1H and 13C NMR spectra were recorded at 200 or 300 and 75 MHz,
respectively; chemical shifts (δ) are reported in ppm and coupling
constants (J) reported in hertz and rounded up to 0.1 Hz. Splitting
patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t),
quartet (q), septuplet (sep), multiplet (m), broad (br), or a combination
of these. Solvents were used as internal standard when assigning NMR
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Table 2. Calculated Thermodynamic Stabilities of 2-Cyanoazetidines
optimized structure
calcd energies (au)
31a
31b
33a
33b
−572.08178889
−572.082558243
−762.78836669
−762.78550949
calcd thermodynamic distribution at 25 °C
exptl distribution
70
30
95
15
40
60
90
10
optimized structure
34a
34b
37a
37b
calcd energies (au)
−723.68316775
−723.68207657
−723.7780645
−723.67599308
calcd thermodynamic distribution at 25 °C
exptl distribution
76
24
85
15
82
18
73
27
chloride (0.1 equiv), and freshly crushed potassium hydroxide (2 equiv).
In the case of substrates 6, 9, and 10, additional DMSO (0.4 mL/mmol)
was also added. The mixture was stirred overnight at room temperature
and then poured into saturated aqueous NH4Cl and extracted with ethyl
acetate. The combined organic layers were then washed with brine, dried
over MgSO4, and evaporated. The residue was purified by flash
chromatography on silica gel with a mixture of PE/EtOAc/MeOH as
eluent.
2-(Phenylamino)ethanol (5). Yield: 1.30 g, 95%. Colorless oil. Rf: 0.2
(PE/EtOAc 7/3). 1H NMR (200 MHz, CDCl3): δ = 7.22 (t, J = 7.9 Hz,
2H, Ph), 6.78 (t, J = 7.3 Hz, 1H, Ph), 6.67 (d, J = 7.6 Hz, 2H, Ph), 3.80 (t,
J = 5.2 Hz, 2H, CH2OH), 3.38 (bs, 2H, OH and NH), 3.28 (t, J = 5.1 Hz,
2H, NCH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.0 (Cq), 129.4
(CAr), 118.1 (CAr), 113.4 (CAr), 61.1 (CH2OH), 46.2 (NCH2) ppm. IR:
νmax = 3350 (b), 2932, 2872, 1600, 1500, 1318, 1260, 1047, 747, 691,
505 cm−1. HRMS (TOF MSES positive mode) m/z calcd for C8H12NO
[MH]+: 138.0919, found 138.0922.
Figure 1. Minimized conformations (MP2 level) for 33a and 34a.
spectra (δ H: CDCl3 7.26 ppm; δ C: CDCl3 77.0 ppm). Assignments for
1
signals from H and 13C in the NMR spectra were validated by two-
dimensional correlated spectroscopy (2D COSY) and heteronuclear
multiple bond correlation (HMBC). IR data were collected with an
ATR-FT-IR spectrometer. All reactions were carried out under argon.
Column chromatography was performed on silica gel (230−400 mesh)
with use of various mixtures of CH2Cl2, EtOAc, petroleum ether (35−60
°C fraction) (PE), and methanol. TLC was performed on Merck
Kieselgel 60 F254 plates. Melting points are uncorrected. THF was
distilled under argon from sodium using benzophenone as indicator.
Dichloromethane was distilled from calcium hydride. Isomeric ratios
were determined by NMR analysis of crude reaction mixtures before
purification.
2-(4-Methoxyphenyl)aminoethanol (6). Yield: 1.45 g, 87%. White
1
solid. Mp: 42−44 °C, Rf: 0.4 (PE/EtOAc 1/1). H NMR (200 MHz,
CDCl3): δ = 6.79 (d, J = 9.0 Hz, 2H, Ar), 6.61 (d, J = 8.9 Hz, 2H, Ar),
3.89−3.63 (m, 5H, OMe and CH2OH), 3.58−3.36 (m, 2H, NH and
OH), 3.18 (t, J = 5.2 Hz, 2H, CH2N) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.5 (Cq), 142.3 (Cq), 114.93 (CAr), 114.89 (CAr), 61.1 (CH2OH),
55.8 (OMe), 47.2 (CH2N) ppm. IR: νmax = 3300, 2926, 2831, 1509,
1229, 1035, 899, 818, 544 cm−1. HRMS (TOF MSES positive mode) m/
z calcd for C9H14NO2 [MH]+: 168.1025, found 168.1020.
General Procedure for the N-Arylation of N-Ethanolamine.10
In a dried, round-bottomed flask were mixed the required iodoaryl
compound (10 mmol, 1 equiv), ethanolamine (3 equiv), copper
2-(3,5-Dimethylphenyl)aminoethanol (7). Yield: 1.44 g, 87%.
1
Colorless oil, Rf: 0.6 (PE/EtOAc 1/1). H NMR (200 MHz, CDCl3):
δ = 6.47 (s, 1H, Ar), 6.33 (s, 2H, Ar), 3.80 (t, 2H, J = 5.3 Hz, CH2OH),
Scheme 7. Synthetic Transformations of N-Aryl-2-cyanoazetidines
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3.34 (s, 2H, NH and OH), 3.28 (t, 2H, J = 5.3 Hz, NCH2), 2.30 (s, 6H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.3 (Cq), 139.0 (Cq),
120.1 (CAr), 111.4 (CAr), 61.2 (CH2OH), 46.3 (NCH2), 21.5 (Me)
ppm. IR: νmax = 3374 (b), 2912, 2850, 1599, 1459, 1334, 1188, 1055,
820, 690 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C10H16NO [MH]+: 166.1232, found 166.1227.
CDCl3): δ = 7.47−7.24 (m, 5H, Ar), 7.15 (t, J = 8.0 Hz, 2H, Ar), 6.74 (t,
J = 7.3 Hz, 1H, Ar), 6.62 (d, J = 8.1 Hz, 2H, Ar), 4.52 (dd, J = 7.1 and 4.2
Hz, 1H, CHPh), 3.95 (dd, J = 11.2 and 4.2 Hz, 1H, CHHOH), 3.76 (dd,
J = 11.1 and 7.1 Hz, 1H, CHHOH), 3.29 (s, 2H, OH and NH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 147.2 (Cq), 140.1 (Cq), 129.2 (CAr), 128.9
(CAr), 127.7 (CAr), 126.8 (CAr), 118.0 (CAr), 114.0 (CAr), 67.3
(CH2OH), 60.0 (CHPh) ppm. IR: νmax =3398 (b), 3050, 3024, 2926,
1600, 1502, 1264, 1064, 1027, 732, 692 cm−1. HRMS (TOF MSES
positive mode) m/z calcd for C14H16NO [MH]+: 214.1232, found
214.1235.
General Procedures for the N-Cyanomethylation of N-
Arylamino Alcohols. Method A/1 (One-Pot, Two-Step Procedure).
A solution of the starting amino alcohol (5 mmol) and paraformalde-
hyde (10 mmol) in MeCN (30 mL) was refluxed for 12 h. After the
solution was cooled to room temperature, TMSCN (10 mmol) was
added, followed by AcOH (10 mmol), and the reaction mixture was
further refluxed for 12 h. After the solution was cooled to room
temperature, water (50 mL) was added, and extraction by EtOAc
followed by usual workup gave a residue that was further purified by flash
chromatography.
2-(Naphthalen-1-ylamino)ethanol (8). Yield: 1.54 g, 82%. White
1
solid. Mp: 44−46 °C, Rf: 0.4 (PE/EtOAc 7/3). H NMR (300 MHz,
CDCl3): δ = 7.96−7.88 (m, 1H, Ar), 7.86−7.78 (m, 1H, Ar), 7.53−7.44
(m, 2H, Ar), 7.41−7.30 (m, 2H, Ar), 6.60 (t, J = 6.9 Hz, 1H, Ph), 4.02 (t,
J = 5.1 Hz, 2H, CH2OH), 3.50 (t, J = 5.1 Hz, 2H, NCH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 143.3 (Cq), 134.4 (Cq), 128.7 (CAr), 126.6 (CAr),
125.9 (CAr), 124.9 (CAr), 123.8 (CAr), 120.1 (CAr), 118.0 (CAr), 104.9
(CAr), 61.0 (CH2OH), 46.2 (NCH2) ppm. IR: νmax = 3329, 3217 (b),
2863, 1582, 1516, 1464, 1454, 1451, 1274, 1210, 1061, 790, 757, 674
cm−1. HRMS (TOF MSES positive mode) m/z calcd for C12H14NO
[MH]+: 188.1075, found 188.1070.
2-(4-Chlorophenyl)aminoethanol (9). Yield: 1.36 g, 79%. White
solid. Mp: 75−77 °C, Rf: 0.3 (PE/EtOAc/MeOH: 70/30/1). 1H NMR
(300 MHz, CDCl3): δ = 7.13 (d, J = 8.8 Hz, 2H, Ar), 6.57 (d, J = 8.8 Hz,
2H, Ar), 3.81 (t, J = 5.3 Hz, 2H, CH2OH), 3.25 (t, J = 5.0 Hz, 2H,
NCH2), 3.08 (s, 2H, NH and OH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 146.7 (Cq), 129.1 (Cq), 122.5 (CAr), 114.3 (CAr), 61.1 (CH2OH), 46.2
(NCH2) ppm. IR: νmax =3301, 3174, 2932, 2847, 1596, 1495, 1269,
1060, 900, 811, 709, 623, 499 cm−1. HRMS (TOF MSES positive mode)
m/z calcd for C8H11ClNO [MH]+: 172.0529, found 172.0531.
2-(4-Bromophenyl)aminoethanol 10. Yield: 1.92 g, 89%. White
solid. Mp: 80−82 °C, Rf: 0.4 (PE/EtOAc/MeOH: 70/30/1). 1H NMR
(300 MHz, CDCl3): δ = 7.26 (d, J = 8.9 Hz, 2H, Ar), 6.52 (d, J = 8.9 Hz,
2H, Ar), 3.81 (t, J = 5.3 Hz, 2H, CH2OH), 3.25 (t, J = 5.0 Hz, 2H,
NCH2), 3.07 (s, 2H, NH and OH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 147.1 (Cq), 132.0 (CAr), 114.8 (CAr), 109.5 (Cq), 61.1 (CH2OH), 46.1
(NCH2) ppm. IR: νmax =3301, 3176 (b), 2936, 2850, 1590, 1494, 1268,
1210, 1059, 899, 807, 681, 608, 510 cm−1. HRMS (TOF MSES positive
mode) m/z calcd for C8H11BrNO [MH]+: 216.0024, found 216.0031.
General Procedure for the N-Arylation of Other Amino
Alcohols.9 In a dried, round-bottomed flask were mixed the required
iodoaryl coumpound (1.2 equiv), the required amino alcohol (10 mmol,
1 equiv), copper iodide (0.05 equiv), and freshly crushed sodium
hydroxide (2 equiv). 2-Propanol was added (10 mL/10 mmol of starting
amino alcohol), and the mixture was stirred overnight at 90 °C for 12 h.
To the resulting suspension was added water (40 mL for 10 mmol of
starting amino alcohol). The layer was extracted with CH2Cl2, washed
with aqueous 1 N NaOH and brine, dried over MgSO4, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography.
(1R,2S)-1-Phenyl-2-(phenylamino)propan-1-ol (11). Yield: 1.48 g,
65%. White solid. Mp: 73−75 °C, Rf: 0.3 (PE/EtOAc/MeOH: 85/15/
1). 1H NMR (300 MHz, CDCl3): δ = 7.47−7.19 (m, 7H, Ar), 6.87−6.65
(m, 3H, Ar), 5.03 (d, J = 3.1 Hz, 1H, CHOH), 3.88−3.76 (m, 1H,
CHMe), 1.05 (d, J = 6.6 Hz, 3H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.9 (Cq), 141.4 (Cq), 129.5 (CAr), 128.4 (CAr), 127.4
(CAr), 125.9 (CAr), 118.2 (CAr), 114.1 (CAr), 74.2 (CHOH), 54.6
(CHMe), 13.9 (Me) ppm. IR: νmax = 3173, 1600, 1498, 1141, 998, 895,
867, 751, 693, 501 cm−1. HRMS (TOF MSES positive mode) m/z calcd
for C15H18NO [MH]+: 228.1388, found 228.1382.
(R)-2-(Phenylamino)butan-1-ol (12). Yield: 1.57 g, 95%. Clear oil.
Rf: 0.3 (PE/EtOAc/MeOH: 70/30/1). 1H NMR (300 MHz, CDCl3): δ
= 7.22 (t, J = 7.8 Hz, 2H, Ar), 6.77 (t, J = 7.5 Hz, 1H, Ar), 6.69 (d, J = 8.4
Hz, 2H, Ar), 3.75 (dd, J = 10.9, 4.2 Hz, 1H, CHHOH), 3.54 (dd, J = 10.9,
5.8 Hz, 1H, CHHOH), 3.48−3.35 (m, 1H, CHCH2Me), 3.08 (bs, 2H,
OH and NH), 1.74−1.41 (m, 2H, CHCH2Me), 0.99 (t, J = 7.5 Hz, 3H,
CHCH2Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.9 (Cq), 129.4
(CAr), 117.8 (CAr), 113.8 (CAr), 64.0 (CH2OH), 56.7 (CHCH2Me),
24.8 (CHCH2Me), 10.7 (Me) ppm. IR: νmax = 3392 (b), 2961, 2929,
2876, 1726, 1600, 1497, 1315, 1246, 1042, 747, 691 cm−1. HRMS (TOF
MSES positive mode) m/z calcd for C10H16NO [MH]+: 166.1232,
found 166.1225.
[(2-Hydroxyethyl)phenylamino]acetonitrile (14). Yield: 720 mg,
1
82%. Colorless oil. Rf: 0.2 (PE/EtOAc 7/3). H NMR (300 MHz,
CDCl3): δ = 7.33 (t, J = 7.9 Hz, 2H, Ph), 6.94 (t, J = 7.6 Hz, 1H, Ph), 6.88
(d, J = 8.1 Hz, 2H, Ph), 4.21 (s, 2H, CH2CN), 3.82 (t, J = 5.3 Hz, 2H,
CH2OH), 3.51 (t, J = 5.3 Hz, 2H, NCH2). 2.73 (bs, 1H, OH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 147.0 (Cq), 129.6 (CAr), 120.2 (CAr),
116.4 (CH2CN), 114.8 (CAr), 60.2 (CH2OH), 54.0 (NCH2), 40.8
(CH2CN) ppm. IR: νmax = 3250 (b), 1592, 1493, 1422, 1369, 1215,
1169, 1048, 1035, 931, 875, 749, 690, 462 cm−1. HRMS (TOF MSES
positive mode) m/z calcd for C10H13N2O [MH]+: 177.1028 , found
177.1032.
[(2-Hydroxyethyl)-(4-methoxyphenyl)amino]acetonitrile (15).
1
Yield: 870 mg, 84%. Colorless oil. Rf: 0.4 (PE/EtOAc 1/1). H NMR
(300 MHz, CDCl3): δ = 6.95 (d, J = 9.2 Hz, 2H, Ar), 6.87 (d, J = 9.2 Hz,
2H, Ar), 4.09 (s, 2H, CH2CN), 3.77 (s, 3H, OMe), 3.74 (t, J = 5.3 Hz,
2H, CH2OH), 3.37 (t, J = 5.3 Hz, 2H, CH2N), 2.44 (s, 1H, OH) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.0 (Cq), 141.4 (Cq), 119.5 and
119.4 (CAr), 116.2 (CH2CN), 114.9 (CAr), 59.8 (CH2OH), 55.6 (OMe),
54.7 (CH2N), 42.71 and 42.67 (CH2CN) ppm. IR: νmax = 3290 (b),
2945, 2920, 2831, 1511, 1252, 1180, 1034, 881, 815, 526 cm−1. HRMS
(TOF MSES positive mode) m/z calcd for C11H15N2O2 [MH]+:
207.1134, found 207.1136.
[(3,5-Dimethylphenyl)-(2-hydroxyethyl)amino]acetonitrile (16).
Yield: 820 mg, 80%. White solid. Mp: 71−73 °C. Rf: 0.6 (PE/EtOAc
1/1). 1H NMR (300 MHz, CDCl3): δ = 6.62 (s, 1H, Ar), 6.54 (s, 2H,
Ar), 4.21 (s, 2H, CH2CN), 3.85 (t, 2H, J = 5.4 Hz, CH2OH), 3.51 (t, 2H,
J = 5.4 Hz, NCH2), 2.32 (s, 6H, Me), 2.11 (s, 1H, OH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 147.2 (Cq), 139.3 (Cq), 122.5 (CAr), 116.4
(CH2CN), 113.2 (CAr), 60.2 (CH2OH), 54.0 (NCH2), 41.0 (CH2CN),
21.7 (Me) ppm. IR: νmax = 3297 (b), 2968, 2923, 1595, 1475, 1357,
1185, 1040, 978, 814, 693 cm−1. HRMS (TOF MSES positive mode) m/
z calcd for C12H17N2O [MH]+: 205.1341, found 205.1350.
[(2-Hydroxyethyl)naphthalen-1-ylamino]acetonitrile (17). Yield:
925 mg, 82%. White solid. Mp: 71−73 °C. Rf: 0.3 (PE/EtOAc 7/3). 1H
NMR (300 MHz, CDCl3): δ = 8.23−8.13 (m, 1H, Ar), 7.97−7.85 (m,
1H, Ar), 7.74 (d, J = 7.7 Hz, 1H, Ar), 7.62−7.40 (m, 4H, Ar), 4.16 (s, 2H,
CH2CN), 3.77 (t, J = 5.1 Hz, 2H, CH2OH), 3.52 (t, J = 5.1 Hz, 2H,
NCH2), 2.02 (bs, 1H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ =
144.3 (Cq), 134.9 (Cq), 129.7 (Cq), 128.9 (CAr), 126.7 (CAr), 126.4
(CAr), 125.7 (CAr), 122.1 (CAr), 119.6 (CAr), 115.5 (CH2CN), 59.9
(CH2OH), 54.9 (NCH2), 44.9 (CH2CN) ppm. IR: νmax = 3441, 3054,
2962, 2886, 2813, 1579, 1394, 1060, 869, 770, 571, 429 cm−1. HRMS
(TOF MSES positive mode) m/z calcd for C14H15N2O [MH]+:
227.1184 , found 227.1180.
Method B/3 (Two-Step Procedure). To a solution of the starting
amino alcohol (2 mmol) and 37% aqueous formaldehyde (175 μL, 2.4
mmol) in CH2Cl2 (10 mL) were added 4 Å molecular sieves (1 g), and
the reaction mixture was allowed to sit for 12 h without stirring.
Filtration and washing (CH2Cl2) gave the crude oxazolidine after
concentration under reduced pressure. This crude compound was taken
(S)-2-Phenyl-2-(phenylamino)ethanol (13). Yield: 1.79 g, 84%.
Clear oil. Rf: 0.5 (PE/EtOAc/MeOH: 70/30/1). 1H NMR (300 MHz,
G
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The Journal of Organic Chemistry
Article
up in AcOH (5 mL), and TMSCN (504 μL, 4 mmol) was added. The
reaction mixture was stirred for 1 h at rt. Addition of water was followed
by extraction with EtOAc, and the combined organic phases were
neutralized by several washings with saturated aqueous Na2CO3. Drying
over MgSO4 of the organic layer and concentration under reduced
pressure gave a residue that was purified by flash chromatography.
[(4-Chlorophenyl)(2-hydroxyethyl)amino]acetonitrile (18). Yield:
850 mg, 81%. White solid. Mp: 60−62 °C. Rf: 0.3 (PE/EtOAc 6/4). 1H
NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 9.1 Hz, 2H, Ar), 6.79 (d, J =
9.1 Hz, 2H, Ar), 4.21 (s, 2H, CH2CN), 3.82 (t, J = 5.2 Hz, 2H, CH2OH),
3.48 (t, J = 5.2 Hz, 2H, NCH2), 2.26 (bs, 1H, OH) ppm. 13C NMR (75
MHz, CDCl3): δ = 145.6 (Cq), 129.5 (CAr), 125.1 (Cq), 116.1
(CH2CN), 115.9 (CAr), 60.1 (CH2OH), 54.1 (NCH2), 40.8 (CH2CN)
ppm. IR: νmax = 3414 (b), 3341 (b), 1591, 1494, 1356, 1207, 1062, 803,
504 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C10H12ClN2O [MH]+: 211.0638, found 211.0643.
Method B/4 (Two-Step Procedure). To a solution of the starting
amino alcohol (2 mmol) and 37% aqueous formaldehyde (175 μL, 2.4
mmol) in CH2Cl2 (10 mL) were added 4 Å molecular sieves (1 g), and
the reaction mixture was allowed to sit for 12 h without stirring.
Filtration and washing (CH2Cl2) gave the crude oxazolidine after
concentration under reduced pressure. This crude compound was taken
up in MeCN (15 mL), and BF3·OEt2 was added dropwise (250 μL, 4
mmol) at 0 °C, followed by TMSCN (500 μL, 4 mmol). The reaction
mixture was stirred for 10 min and then quenched by addition of water
(20 mL). The reaction mixture was extracted with EtOAc, and the
combined organic phases were neutralized by several washings with
saturated aqueous Na2CO3. Drying over MgSO4 of the organic layer and
concentration under reduced pressure gave a residue that was purified by
flash chromatography.
[(4-Bromophenyl)(2-hydroxyethyl)amino]acetonitrile (19). Yield:
800 mg, 64%. White solid. Mp: 66−68 °C. Rf: 0.3 (PE/EtOAc 6/4). 1H
NMR (300 MHz, CDCl3): δ = 7.39 (d, J = 9.1 Hz, 2H, Ar), 6.74 (d, J =
9.1 Hz, 2H, Ar), 4.22 (s, 2H, CH2CN), 3.83 (t, J = 5.2 Hz, 2H, CH2OH),
3.49 (t, J = 5.2 Hz, 2H, NCH2), 2.12 (bs, 1H, OH) ppm. 13C NMR (75
MHz, CDCl3): δ = 146.0 (Cq), 132.4 (CAr), 116.3 (CAr), 116.1
(CH2CN), 112.4 (Cq), 60.1 (CH2OH), 54.0 (NCH2), 40.7 (CH2CN)
ppm. IR: νmax = 3414 (b), 3332 (b), 2923, 2872, 1584, 1491, 1355, 1208,
1062, 801 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C10H12BrN2O [MH]+: 255.0133, found 255.0141.
Method A/4 (One-Pot, Two-Step Procedure). A solution of the
starting amino alcohol (5 mmol) and paraformaldehyde (10 mmol) in
MeCN (30 mL) was refluxed for 12 h. After the solution was cooled to
room temperature, BF3·OEt2 was added dropwise (250 μL, 4 mmol),
followed by TMSCN (500 μL, 4 mmol). The reaction mixture was
stirred for 10 min and then quenched by addition of water (20 mL). The
reaction mixture was extracted with EtOAc, and the combined organic
phases were neutralized by several washings with saturated aqueous
Na2CO3. Drying over MgSO4 of the organic layer and concentration
under reduced pressure gave a residue that was purified by flash
chromatography.
δ = 147.9 (Cq), 129.6 (CAr), 119.7 (CAr), 117.7 (CH2CN), 114.7 (CAr),
62.7 (CH2OH), 62.0 (CHCH2Me), 34.0 (CH2CN), 21.9 (CHCH2Me),
11.3 (Me) ppm. IR: νmax = 3420 (b), 2964, 2932, 2869, 1597, 1502,
1039, 748, 690 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C12H17N2O [MH]+: 205.1341, found 205.1337
Method C/2 (Two-Step Procedure). A solution of the starting amino
alcohol (5 mmol), p-TsOH (2 mol %), and paraformaldehyde (300 mg,
10 mmol) in benzene (100 mL) was azetropically refluxed for 12 h. After
being cooled to room temperature, the mixture was neutralized by
washing with saturated aqueous NaHCO3, dried over MgSO4, and
concentrated under reduced pressure. The obtained crude oxazolidine
was rapidly passed through a short pad of silica gel, eluting with EP/
EtOAc 80/20 to remove small quantities of unreacted amino alcohol.
The oxazolidine was then dissolved in AcOH (50 mL), and solid KCN
(2.6 g, 40 mmol, 8 equiv) was added cautiously portionwise (Caution:
evolved HCN was trapped in an aqueous solution of 1 M NaOH). The
reaction mixture was heated to 70−80 °C until complete conversion of
the oxazolidine was observed by TLC (1−2 h). After the mixture was
cooled to room temperature, water was added (150 mL), and the
resulting mixture was extracted with EtOAc. The combined layers were
neutralized by several washings with saturated aqueous K2CO3 solution,
dried over MgSO4, and concentrated under reduced pressure. The
residue was further purified by flash chromatography.
(S)-[(2-Hydroxy-1-phenylethyl)phenylamino]acetonitrile (22).
Yield: 1.03 g, 82%. White solid. Mp: 90−92 °C. Rf: 0.3 (PE/EtOAc
75/25). [α]D20 −108 (c 1.9, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.46−7.29 (m, 7H, Ph), 7.07 (d, J = 7.8 Hz, 2H, Ph), 7.01(t, J = 7.4 Hz,
1H, Ph), 4.97 (t, J = 5.8 Hz, 1H, CHPh), 4.21−3.98 (m, 4H, CH2CN
and CH2OH), 1.97 (dd, J = 6.6, 5.4 Hz, 1H, OH) ppm. 13C NMR (75
MHz, CDCl3): δ = 147.0 (Cq), 142.1 (Cq), 129.7 (CAr), 128.6 (CAr),
127.7 (CAr), 125.7 (CAr), 119.7 (CAr), 117.9 (CH2CN), 114.6 (CAr),
75.5 (CHOH), 58.9 (CHMe), 35.6 (CH2CN), 10.6 (Me) ppm. IR: νmax
= 3474 (b), 2936, 1594, 1500, 1365, 1245, 1161, 1065, 958, 745, 690,
511 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C16H17N2O [MH]+: 253.1341, found 253.1353.
Method D/2 (Two-Step Procedure). A solution of the starting amino
alcohol (5 mmol), p-TsOH (2 mol %), and the required aromatic
aldehyde (5 mmol) in benzene (100 mL) was azeotropically refluxed for
12 h. After being cooled to room temperature, the mixture was
neutralized by washing with saturated aqueous NaHCO3, dried over
MgSO4, and concentrated under reduced pressure. The obtained crude
oxazolidine was recrystallized from i-PrOH (20 mL) to remove small
quantities of unreacted amino alcohol. The oxazolidine was then treated
with KCN in AcOH, following method 2 above.
(4-Bromophenyl)[(2-hydroxyethyl)phenylamino]acetonitrile (23).
Yield: 1.31 g, 79%. Oil. Rf: 0.3 (PE/EtOAc 75/25). 1H NMR (300 MHz,
CDCl3): δ = 7.55 (d, J = 8.6 Hz, 2H, Ar), 7.42 (d, J = 8.2 Hz, 2H), 7.32 (t,
J = 8.0 Hz, 2H), 7.11−7.02 (m, 3H, Ar), 5.62 (s, 1H, CHCN), 3.70−3.56
(m, 2H, CH2OH), 3.49 (dt, J = 14.2, 5.0 Hz, 1H, NCHH), 3.28 (ddd, J =
14.2, 6.8, 5.5 Hz, 1H, NCHH), 1.92 (bs, 1H, OH) ppm. 13C NMR (75
MHz, CDCl3): δ = 146.4 (Cq), 132.5 (Cq), 132.3 (CAr), 129.6 (CAr),
129.1 (CAr), 123.4 (Cq), 123.1 (CAr), 120.0 (CAr), 116.6 (CHCN), 59.7
(CH2OH), 59.3 (CHCN), 51.5 (NCH2) ppm. IR: νmax = 3395 (b), 1596,
1486, 1071, 1009, 747, 693 cm−1. HRMS (TOF MSES positive mode)
m/z calcd for C16H16BrN2O [MH]+: 331.0446, found 331.0443.
Azetidine Synthesis. Two-Step Procedure via an Intermediate
Mesylate. To a solution of the starting amino alcohol (2 mmol) and
triethylamine (0.7 mL, 5 mmol) in CH2Cl2 (6 mL) cooled to 0 °C was
added dropwise methanesulfonyl chloride (186 μL, 2.4 mmol). The
reaction mixture was stirred at 0 °C for 30 min, warmed to rt, and stirred
for an additional 30 min. The mixture was quenched by addition of water
(15 mL) and extracted with CH2Cl2. The combined organic layers were
washed with 2% aqueous HCl and brine, dried over MgSO4, and
concentrated under reduced pressure. The obtained mesylate was next
dissolved in dry THF (15 mL), and t-BuOK (270 mg, 2.4 mmol) was
added at 0 °C. The reaction mixture was allowed to warm to room
temperature and then quenched with water, followed by usual workup
(EtOAc). The crude azetidine was purified by flash chromatography.
1-Phenylazetidine-2-carbonitrile (25). Yield: 295 mg, 92%. White
solid. Mp: 78−80 °C. Rf: 0.6 (PE/EtOAc 85/15). 1H NMR (300 MHz,
(1R,2S)-[(2-Hydroxy-1-methyl-2-phenylethyl)phenylamino]-
acetonitrile (20). Yield: 1.08 g, 81%. Oil. Rf: 0.5 (PE/EtOAc 75/25).
[α]D20 −23 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.46−7.26
(m, 7H, Ar), 7.03−6.87 (m, 3H, Ar), 5.05 (d, J = 2.5 Hz, 1H, CHOH),
4.37 and 4.24 (two d, J = 18 Hz, 2H, CH2CN), 4.09 (qd, J = 6.9 and 2.8
Hz, 1H, CHMe), 2.42 (s, 1H, OH), 1.24 (d, J = 6.9 Hz, 3H, Me) ppm.
13C NMR (75 MHz, CDCl3): δ = 147.0 (Cq), 142.1 (Cq), 129.7 (CAr),
128.6 (CAr), 127.7 (CAr), 125.7 (CAr), 119.7 (CAr), 117.9 (CH2CN),
114.6 (CAr), 75.5 (CHOH), 58.9 (CHMe), 35.6 (CH2CN), 10.6 (Me)
ppm. IR: νmax = 3449 (b), 3059, 3024, 2981, 1596, 1501, 1246, 1174,
1026, 742, 690 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C17H19N2O [MH]+: 267.1497, found 267.1500.
(R)-[(1-Hydroxymethylpropyl)phenylamino]acetonitrile (21).
Yield: 870 mg, 85%. Oil. Rf: 0.3 (PE/EtOAc/MeOH 75/25/1).
[α]D20 + 47 (c 1.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.32 (dd, J
= 8.7 and 7.4 Hz, 2H, Ph), 6.98−6.87 (m, 3H, Ph), 4.19 and 4.12 (two d,
J = 18.0 Hz, 2H, CH2CN), 3.90−3.66 (m, 3H, CH2OH and
CHCH2Me), 2.22 (bs, 1H, OH), 1.66 (q, J = 7.3 Hz, 2H, CHCH2Me),
0.97 (t, J = 7.4 Hz, 3H, CHCH2Me) ppm. 13C NMR (75 MHz, CDCl3):
H
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The Journal of Organic Chemistry
Article
CDCl3): δ = 7.31 (t, J = 8.0 Hz, 2H, Ph), 6.92 (t, J = 7.4 Hz, 1H, Ph), 6.61
(d, J = 7.8 Hz, 2H, Ph), 4.58 (dd, J = 8.1 and 6.6 Hz, 1H, CHCN), 4.09−
3.98 (m, 1H, NCHH), 3.79 (q, J = 7.4 Hz, 1H, NCHH). 2.90−2.60 (m,
2H, NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.1 (Cq),
129.2 (CAr), 119.7 (CAr), 118.8 (CHCN), 112.0 (CAr), 50.6 (NCH2),
50.4 (CHCN), 22.5 (NCH2CH2) ppm. IR: νmax =3031, 2967, 2872,
1701, 1598, 1500, 1323, 755, 692, 515 cm−1. HRMS (TOF MSES
positive mode) m/z calcd for C10H11N2 [MH]+: 159.0922, found
159.0923.
1H, CH2CHCN), 2.47 (dt, J = 11.2 and 7.3 Hz, 1H, CH2CHCN), 2.09−
1.93 (m, 1H, CHCH2Me), 1.95−1.78 (m, 1H, CHCH2Me), 1.01 (t, J =
7.5 Hz, 3H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.0 (Cq),
129.3 (CAr), 120.0 (CAr), 119.4 (CHCN), 112.3 (CAr), 64.3
(CHCH2Me), 47.9 (CHCN), 29.3 (CHCH2Me), 27.9 (CH2CHCN),
8.3 (Me) ppm. IR: νmax = 2972, 2930, 2875, 1652, 1576, 1405, 750 cm−1.
HRMS (TOF MSES positive mode) m/z calcd for C12H15N2 [MH]+:
187.1235, found 187.1240. Minor epimer 31b. Oil. Rf: 0.45 (PE/EtOAc
95/5). [α]D20 −381 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
7.30 (t, J = 7.8 Hz, 2H, Ar), 6.90 (t, J = 7.4 Hz, 1H, Ar), 6.61 (d, J = 8.3
Hz, 2H, Ar), 4.79 (dd, J = 8.3 and 3.5 Hz, 1H, CHCN), 4.31 (qd, J = 7.8
and 3.6 Hz, 1H, CHCH2Me), 2.71−2.59 (m, 1H, CH2CHCN), 2.49 (dt,
J = 11.1 and 7.7 Hz, 1H, CH2CHCN), 2.10−1.94 (m, 1H, CHCH2Me),
1-(4-Methoxyphenyl)azetidine-2-carbonitrile (26). Yield: 350 mg,
1
94%. White solid. Mp: 49−51 °C. Rf: 0.4 (PE/EtOAc 9/1). H NMR
(300 MHz, CDCl3): δ = 6.87 (d, J = 9.0 Hz, 2H, Ar), 6.56 (d, J = 9.0 Hz,
2H, Ar), 4.52 (dd, J = 8.3, 6.7 Hz, 1H, CHCN), 4.03−3.95 (m, 1H,
NCHH), 3.86−3.68 (m, 4H, NCHH and OMe), 2.87−2.59 (m, 2H,
NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.6 (Cq), 143.5
(Cq), 118.9 (CHCN), 114.8 (CAr), 113.3 (CAr), 55.7 (OMe), 50.9
(CHCN and NCH2), 22.5 (NCH2CH2) ppm. IR: νmax = 2955, 2869,
2831, 1504, 1440, 1237, 1028, 827, 619 cm−1. HRMS (TOF MSES
positive mode) m/z calcd for C11H13N2O [MH]+: 189.1028, found
189.1026.
1.78−1.59 (m, 1H, CHCH2Me), 0.94 (t, J = 7.5 Hz, 3H, Me) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 146.7 (Cq), 129.2 (CAr), 119.7 (CAr),
118.3 (CHCN), 112.9 (CAr), 63.6 (CHCH2Me), 48.3 (CHCN), 27.9
(CHCH2Me), 27.5 (CH2CHCN), 8.2 (Me) ppm. IR: νmax = 3317 (b),
2964, 2929, 2877, 1651, 1600, 1577, 1406, 1041, 752, 639 cm−1. HRMS
(TOF MSES positive mode) m/z calcd for C12H15N2 [MH]+ 187.1235,
found 187.1237.
1-(3,5-Dimethylphenyl)azetidine-2-carbonitrile (27). Yield: 325
mg, 87%. White solid. Mp: 99−101 °C. Rf: 0.3 (PE/EtOAc 95/5). 1H
NMR (300 MHz, CDCl3): δ = 6.56 (s, 1H, Ar), 6.23 (s, 2H, Ar), 4.56
(dd, J = 8.4, 6.8 Hz, 1H, CHCN), 4.07−3.98 (m, 1H, NCHH), 3.77 (q, J
= 7.5 Hz, 1H, NCHH), 2.89−2.75 (m, 1H, NCH2CHH), 2.74−2.60 (m,
1H, NCH2CHH), 2.31 (s, 6H, Me) ppm. 13C NMR (75 MHz, CDCl3):
δ = 149.4 (Cq), 139.1 (Cq), 121.8 (CAr), 118.9 (CHCN), 109.8 (CAr),
50.6 (NCH2), 50.4 (CHCN), 22.6 (NCH2CH2), 21.5 (Me) ppm. IR:
νmax = 2961, 2910, 2875, 1594, 1473, 1350, 1204, 823 cm−1. HRMS
(TOF MSES positive mode) m/z calcd for C12H15N2 [MH]+: 187.1235,
found 187.1237.
(1R,2S)-((2-Chloro-1-methyl-2-phenylethyl)phenylamino)-
acetonitrile (32). This compound was prepared following the above
procedure for 25 starting from 20. The expected intermediate mesylate
was completely transformed into the corresponding chloride. However,
32 is unstable on silica gel, and after purification by flash
chromatography, a 1/1 mixture of chloride 32 and alcohol 20 was
obtained. Rf: 0.6 (PE/EtOAc 95/5). 1H NMR (300 MHz, CDCl3): δ =
7.48−7.28 (m, 7HOH and 7HCl, Ph), 6.96 (m, 3HOH and 3HCl, Ph), 5.21
(d, J = 5.1 Hz, 1HCl), 5.09 (d, J = 2.7 Hz, 1HOH, CHOH), 4.43−4.24 (m,
2HOH and 2HCl, CH2OHCN CHHClCN and CHClMe), 4.16−4.00 (m,
1HOH and 1HCl, CHClHCN and CHOHMe), 2.23 (s, 1H OH, OH), 1.50
(d, J = 6.7 Hz, 3HCl, Me), 1.26 (d, J = 6.9 Hz, 3HOH, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 146.2 (Cq), 138.6 (Cq), 128.7 (CAr), 127.2 (CAr),
120.4 (CAr), 117.1 (CH2CN), 115.2 (CAr), 66.4 (CHCl), 60.1 (CHMe),
35.4 (CH2CN), 13.3 (Me) ppm of HRMS (TOF MSES positive mode)
m/z calcd for C17H18ClN2 [MH]+: 285.1159, found 285.1150.
One-Pot, Two-Step Procedure via an Intermediate Chloride or
Mesylate. To a solution of the starting amino alcohol (2 mmol) and
triethylamine (0.7 mL, 5 mmol) in THF (6 mL) cooled to 0 °C was
added dropwise methanesulfonyl chloride (186 μL, 2.4 mmol). The
reaction mixture was stirred to 0 °C for 30 min, warmed to rt, and stirred
for an additional 30 min. It was then cooled to 0 °C, and t-BuOK (900
mg, 8 mmol) was added portionwise at 0 °C. The reaction mixture was
allowed to warm to room temperature, and addition of water was
followed by usual workup (EtOAc). The crude azetidine was purified by
flash chromatography.
1-(Naphthalen-1-yl)azetidine-2-carbonitrile (28). Yield: 340 mg,
82%. White solid. Mp: 130−132 °C. Rf: 0.4 (PE/EtOAc 9/1). 1H NMR
(300 MHz, CDCl3): δ = 8.03−7.77 (m, 2H, Ar), 7.56−7.38 (m, 4H, Ar),
6.76 (d, J = 7.4 Hz, 1H, Ar), 4.93 (dd, J = 8.3 and 6.8 Hz, 1H, CHCN),
4.55−4.46 (m, 1H, NCHH), 3.87 (q, J = 5.1 Hz, 1H, NCHH), 2.92−
2.78 (m, 1H, NCH2CHH), 2.78−2.64 (m, 1H, NCH2CHH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 145.1 (Cq), 134.8 (Cq), 128.7 (Cq), 126.2
(CAr), 125.6 (CAr), 125.3 (CAr), 125.2 (CAr), 123.0 (CAr), 122.5 (CAr),
118.5 (CHCN), 109.6 (CAr), 54.4 (NCH2), 51.0 (CHCN), 22.8
(NCH2CH2) ppm. IR: νmax = 3053, 2993, 2958, 2910, 2888, 2239, 1573,
1397, 1285, 1070, 1022, 799, 770 cm−1. HRMS (TOF MSES positive
mode) m/z calcd for C14H13N2 [MH]+ 209.1079, found 209.1074.
1-(4-Chlorophenyl)azetidine-2-carbonitrile (29). Yield: 285 mg,
1
74%. White solid. Mp: 64−66 °C. Rf: 0.3 (PE/EtOAc 9/1). H NMR
(300 MHz, CDCl3): δ = 7.22 (d, J = 8.8 Hz, 2H, Ar), 6.50 (d, J = 8.8 Hz,
2H, Ar), 4.57 (dd, J = 8.2, 6.7 Hz, 1H, CHCN), 4.08−3.93 (m, 1H,
NCHH), 3.77 (q, J = 7.4 Hz, 1H, NCHH), 2.90−2.62 (m, 2H,
NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.5 (Cq), 129.2
(CAr), 124.8 (Cq), 118.4 (CHCN), 113.2 (CAr), 50.6 (NCH2), 50.5
(CHCN), 22.4 (NCH2CH2) ppm. IR: νmax = 2983, 2879, 1597, 1492,
1326, 1092, 812, 506 cm−1. HRMS (TOF MSES positive mode) m/z
calcd for C10H10ClN2 [MH]+: 193.0533, found 193.0525.
(2S,3S,4S)-4-Methyl-1,3-diphenylazetidine-2-carbonitrile (33a)
and (2R,3S,4S)-4-Methyl-1,3-diphenylazetidine-2-carbonitrile (33b).
Yield: 380 mg, 76%, Crude ratio: 60:40 for 33a:33b. These epimers were
separated by flash chromatography. Major epimer 33a (68%). White
solid. Mp: 100−102 °C. Rf: 0.45 (PE/EtOAc 95/5). [α]D20 +50 (c 1.0,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.45−7.23 (m, 7H, Ph), 6.97
(t, J = 7.4 Hz, 1H, Ph), 6.79 (d, J = 7.9 Hz, 2H, Ph), 4.38 (d, J = 7.4 Hz,
1H, CHCN), 4.16 (q, J = 6.2 Hz, 1H, CHMe), 3.83 (t, J = 7.3 Hz, 1H,
CHPh), 1.70 (d, J = 6.0 Hz, 3H, Me) ppm. 13C NMR (75 MHz, CDCl3):
δ = 150.2 (Cq), 137.1 (Cq), 129.5 (CAr), 129.0 (CAr), 128.2 (CAr), 127.1
(CAr), 120.6 (CAr), 118.9 (CHCN), 112.8 (CAr), 66.6 (CHMe), 55.2
(CHCN), 49.6 (CHPh), 22.7 (Me) ppm. IR: νmax = 2958, 2876, 1596,
1493, 1321, 1129, 755, 659 cm−1. HRMS (TOF MSES positive mode)
m/z calcd for C17H17N2 [MH]+: 249.1392, found 249.1393. Suitable
crystals of 33a for X-ray crystallography were obtained by slow
evaporation of an i-PrOH solution. Minor epimer 33b (8%). Oil. Rf: 0.25
1-(4-Bromophenyl)azetidine-2-carbonitrile (30). Yield: 340 mg,
1
72%. White solid. Mp: 82−84 °C. Rf: 0.2 (PE/EtOAc 9/1). H NMR
(300 MHz, CDCl3): δ = 7.36 (d, J = 8.9 Hz, 2H, Ar), 6.45 (d, J = 8.9 Hz,
2H, Ar), 4.57 (dd, J = 8.3, 6.6 Hz, 1H, CHCN), 4.08−3.95 (m, 1H,
NCHH), 3.77 (q, J = 7.4 Hz, 1H, NCHH), 2.90−2.62 (m, 2H,
NCH2CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 147.9 (Cq), 132.0
(CAr), 118.3 (CHCN), 113.7 (CAr), 112.0 (Cq), 50.6 (NCH2), 50.4
(CHCN), 22.4 (NCH2CH2) ppm. IR: νmax = 2980, 2872, 1591, 1489,
1329, 808, 500 cm−1. HRMS (TOF MSES positive mode) m/z calcd for
C10H10BrN2 [MH]+: 237.0027, found 237.0032.
1
(PE/EtOAc 95/5). H NMR (200 MHz, CDCl3): δ = 7.55−7.10 (m,
7H, Ph), 6.94 (t, J = 7.4 Hz, 1H, Ph), 6.70 (d, J = 7.2 Hz, 2H, Ph), 5.21
(d, J = 8.2 Hz, 1H, CHCN), 4.61 (p, J = 6.2 Hz, 1H, CHMe), 3.84 (t, J =
7.7 Hz, 1H, CHPh), 1.58 (d, J = 6.0 Hz, 3H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.4 (Cq), 135.3 (Cq), 129.3 (CAr), 128.8 (CAr), 128.3
(CAr), 120.2 (CAr), 115.9 (CHCN), 113.6 (CAr), 64.0 (CHMe), 55.9
(CHCN), 46.8 (CHPh), 20.6 (Me) ppm. HRMS (TOF MSES positive
mode) m/z calcd for C17H17N2 [MH]+: 249.1392, found 249.1390
(2S,4R)-4-Ethyl-1-phenylazetidine-2-carbonitrile (31a and 31b).
Yield: 310 mg, 83%. Crude ratio: 60:40 for 31a:31b. These epimers were
separated by preparative TLC. Major epimer 31a. Oil. Rf: 0.55 (PE/
20
EtOAc 95/5). [α]D +136 (c 0.7, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.29 (t, J = 7.8 Hz, 2H, Ph), 6.91 (t, J = 7.4 Hz, 1H, Ph), 6.68
(d, J = 7.9 Hz, 2H, Ph), 4.36 (dd, J = 8.7 and 7.5 Hz, 1H, CHCN), 3.98
(qd, J = 7.9 and 3.9 Hz, 1H, CHCH2Me), 2.76 (dt, J = 11.1 and 8.4 Hz,
I
DOI: 10.1021/acs.joc.6b00169
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The Journal of Organic Chemistry
Article
(2S,4R)-1,4-Diphenylazetidine-2-carbonitrile (34a) and (2R,4R)-
1,4-Diphenylazetidine-2-carbonitrile (34b). Yield: 330 mg, 70%.
Crude ratio: 82:18 for 34a:34b. Pasty solid. Rf: 0.5 (PE/EtOAc 9/1).
(CAr), 129.0 (CAr), 128.4 (CAr), 128.1 (CAr), 120.0 (CAr), 116.5
(CHCN), 112.4 (CAr), 57.1 (CHCN), 57.0 (NCH2), 38.5 (CHPh) ppm.
HRMS (TOF MSES positive mode) m/z calcd for C16H15N2 [MH]+:
235.1235, found 235.1230
1
These isomers could not be separated by chromatography. H NMR
(300 MHz, CDCl3): δ = 7.44 (d, J = 7.0 Hz, 2HM, Ar), 7.39−7.21 (m,
3HM and 5Hm, Ar), 7.12 (t, J = 7.8 Hz, 2HM and 2Hm, Ar), 6.79 (t, J = 7.3
Hz, 1HM and 1Hm, Ar), 6.50 (d, J = 8.0 Hz, 2HM, Ar), 6.42 (d, J = 8.0 Hz,
2Hm, Ar), 5.14 (t, J = 7.8 Hz, 1Hm, CHmCN), 4.88−4.71 (m, 1HM and
1Hm, CHMCN and CHmPh), 4.42 (t, J = 8.0 Hz, 1HM, CHMPh), 2.96 (dt,
J = 11.0, 8.2 Hz, 1HM, CHHMCHCN), 2.82 (ddd, J = 10.5, 7.7, 2.6 Hz,
1Hm, CHHmCHCN), 2.67−2.48 (m, 1HM and 1Hm, CHMHCHCN and
CHmHCHCN) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.5 (CqM),
146.4 (Cqm), 141.3 (CqM), 140.9 (Cqm), 129.3 (CArM), 129.2 (CArm),
129.1 (CArM), 129.0 (CArm), 128.43 (CArM), 128.37 (CArm), 126.1
(CArM), 126.0 (CArm), 120.5 (CArM), 120.2 (CArm), 119.1 (CHCMN),
118.0 (CHCmN), 113.3 (CArm), 112.7 (CArM), 65.8 (CMHPh), 65.5
(CmHPh), 48.5 (CmHCN), 47.4 (CMHCN), 33.0 (CmH2), 32.8 (CMH2)
ppm. IR: νmax = 3062, 3031, 2968, 2913, 2876, 1598, 1498, 1322, 751,
693, 1041, 752, 639 cm−1. HRMS (TOF MSES positive mode) m/z
calcd for C16H15N2 [MH]+: 235.1235, found 235.1240. Suitable crystals
of 34a for X-ray crystallography were obtained by slow evaporation of a
CHCl3 solution of the mixture.
2-(4-Bromophenyl)-1-phenylazetidine-2-carbonitrile (35). Yield:
500 mg, 80%. White solid. Mp: 90−92 °C. Rf: 0.6 (PE/EtOAc 95/5). 1H
NMR (300 MHz, CDCl3): δ = 7.60 (s, 4H, Ar), 7.24 (dd, J = 8.7, 7.5 Hz,
2H, Ph), 6.91 (t, J = 7.4 Hz, 1H, Ph), 6.47 (d, J = 7.7 Hz, 2H, Ph), 4.11−
4.00 (m, 2H, NCH2), 2.99 (ddd, J = 10.9, 6.8, 3.9 Hz, 1H, NCH2CHH),
2.71 (dt, J = 11.0, 8.6 Hz, 1H, NCH2CHH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 146.5 (Cq), 137.4 (Cq), 132.4 (CAr), 129.1 (CAr), 127.0
(CAr), 123.4 (Cq), 120.3 (CAr), 118.5 (CCN), 112.9 (CAr), 66.7 (CCN),
47.5 (NCH2), 35.0 (NCH2CH2) ppm. IR: νmax =2974, 2948, 2875, 1599,
1484, 1315, 822, 761, 695 cm−1. HRMS (TOF MSES positive mode) m/
z calcd for C16H14BrN2 [MH]+: 313.0340, found 313.0347.
(2R)-[(2-Chloro-2-phenylethyl)phenylamino]acetonitrile (36).
This compound was obtained after refluxing a solution of the
intermediate mesylate obtained from 22 (2 mmol) prepared without
isolation as reported above for 20, but using as solvent acetonitrile
instead of THF. It was purified by flash chromatography. Yield: 495 mg,
92%. Oil. Rf: 0.4 (PE/EtOAc 9/1). [α]D20 −8 (c 1.1, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 7.50−7.29 (m, 7H, Ph), 6.97 (t, J = 7.4 Hz, 1H,
Ph), 6.83 (d, J = 7.9 Hz, 2H, Ph), 5.13 (t, J = 7.0 Hz, 1H, CHCl), 4.20−
3.76 (m, 4H, CH2CN and CH2CHCl) ppm. 13C NMR (75 MHz,
CDCl3): δ = 145.9 (Cq), 138.8 (Cq), 129.8 (CAr), 129.2 (CAr), 129.1
(CAr), 127.3 (CAr), 120.2 (CAr), 115.8 (CH2CN), 113.8 (CAr), 60.5
(CH2CHCl), 60.1 (CHCl), 40.6 (CH2CN) ppm. IR: νmax = 3031, 1598,
1503, 1348, 1208, 1174, 748, 693 cm−1. HRMS (TOF MSES positive
mode) m/z calcd for C16H16ClN2 [MH]+: 271.1002, found 271.1013
(2R,3R)-1,3-Diphenylazetidine-2-carbonitrile (37a) and (2S,3R)-
1,3-Diphenylazetidine-2-carbonitrile (37b). To a solution of the above
chloride 36 (100 mg, 0.37 mmol) in THF (10 mL) was added
portionwise at 0 °C t-BuOK (62 mg, 0.55 mmol, 1.5 equiv). The
reaction mixture was stirred for 20 min and allowed to reach room
temperature. Addition of water was followed by usual workup (EtOAc).
The crude azetidines were purified by flash chromatography. Yield: 77
mg, 89%. Crude ratio: 73:27 for 37a:37b. These epimers were separated
by flash chromatography. Major epimer 37a (65%). Oil. Rf: 0.6 (PE/
EtOAc 9/1). [α]D20 −126 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3):
δ = 7.46−7.30 (m, 7H, Ph), 6.97 (t, J = 7.4 Hz, 1H, Ph), 6.72 (d, J = 7.7
Hz, 2H, Ph), 4.56 (d, J = 6.6 Hz, 1H, CHCN), 4.44 (dd, J = 8.1, 6.6 Hz,
1H, NCHH), 4.34 (q, J = 7.2 Hz, 1H, CHPh), 3.94 (t, J = 6.7 Hz, 1H,
NCHH) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.2 (Cq), 137.9 (Cq),
129.4 (CAr), 129.1 (CAr), 128.2 (CAr), 127.0 (CAr), 120.2 (CAr), 118.3
(CHCN), 112.4 (CAr), 57.6 (CHCN), 57.3 (NCH2), 41.1 (CHPh) ppm.
IR: νmax = 3029, 2865, 1598, 1497, 1319, 748, 691 cm−1. HRMS (TOF
MSES positive mode) m/z calcd for C16H15N2 [MH]+: 235.1235, found
235.1241. Minor epimer 37b (24%). Oil. Rf: 0.4 (PE/EtOAc 9/1).
[α]D20 +92 (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.62−7.18
(m, 7H, Ph), 6.95 (t, J = 7.2 Hz, 1H, Ph), 6.70 (d, J = 7.8 Hz, 1H, Ph),
5.02 (d, J = 8.1 Hz, 1H, CHCN), 4.27−4.03 (m, 3H, CHPh and NCH2)
ppm. 13C NMR (75 MHz, CDCl3): δ = 148.7 (Cq), 137.2 (Cq), 129.3
Procedure for Azetidinium Salt Formation. Azetidine 25 (200
mg, 1.3 mmol) was dissolved in DCM (4 mL), and methyl
trifluoromethanesulfonate (250 μL, 2.5 mmol) was added dropwise.
The mixture was stirred under argon for 12 h and then poured into Et2O
(5 mL). The precipitate was filtered and washed with cold Et2O (10
mL). The white solid was dried under vacuum.
2-Cyano-1-methyl-1-phenylazetidin-1-ium Methanesulfonate 38.
Yield: 360 mg, 89%. Ratio Major/minor: 1/0.22. 1H NMR (300 MHz,
acetone d6): δ = 7.95 (d, J = 8.3 Hz, 2Hm, Ph), 7.80−7.60 (m, 5Hm and
3HM, Ph), 6.64 (t, J = 9.6 Hz, 1HM, CHCN), 6.34 (dt, J = 6.4, 2.8 Hz,
1Hm, CHCN), 5.78 (q, J = 10.1 Hz, 1Hm, NCHH), 5.40 (q, J = 9.8 Hz,
1HM, NCHH), 5.07 (m, 1HM and 1Hm, NCHH), 4.05 (s, 1Hm, Me),
4.04 (s, 1HM, Me), 4.00−3.85 (m, 1Hm, NCH2CHH), 3.85−3.67 (m,
1HM, NCH2CHH), 3.32−3.13 (m, 1HM, NCH2CHH), 3.10−2.96 (m,
1Hm, NCH2CHH) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.4 (Cq),
131.9 (CAr), 131.7 (CAr), 131.61 (CAr), 131.56 (CAr), 131.3 (CAr), 124.2
(CF3), 123.0 (CF3), 121.7 (CAr), 120.1 (CAr), 120.0 (CF3), 114.3
(CHCmN), 113.4 (CHCMN), 68.7 (CmHCN), 67.7 (NCMH2), 66.3
(NCmH2), 63.7 (CMHCN), 57.9 (Mem), 55.1 (MeM), 22.5
(NCH2CMH2), 22.2 (NCH2CmH2) ppm. IR: νmax = 2959, 1247, 1148,
1026, 759, 635, 515 cm−1. HRMS (TOF MSES positive mode) m/z
calcd for C11H13N2 [M]+: 173.1079, found 173.1079
Procedure for Azetidinium Salt Ring Opening. Azetidinium salt
38 (161 mg, 0.5 mmol) was dissolved in freshly distilled DMF (2.5 mL),
and NaN3 (325 mg, 5 mmol) was added portionwise. The mixture was
stirred for 12 h under argon and then quenched with water (15 mL) and
EtOAc (15 mL). Extraction by EtOAc followed by usual workup gave a
residue that was further purified by flash chromatography.
2-Azido-4-(methyl(phenyl)amino)butanenitrile (39). Yield: 47 mg,
44%. Oil. Rf: 0.4 (EP/EtOAc 9/1). 1H NMR (300 MHz, CDCl3): δ =
7.30 (t, 2H, Ph), 6.85−6.74 (m, 3H, Ph), 4.32 (dd, J = 7.4, 6.6 Hz, 1H,
CHCN), 3.63−3.45 (m, 2H, CH2NPh), 2.96 (s, 3H, Me), 2.24−2.01
(m, 2H, CH2CHCN) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.8
(Cq), 129.5 (CAr), 117.7 (CAr), 116.2 (CHCN), 113.0 (CAr), 48.9
(CHCN), 48.4 (CH2NPh), 38.9 (Me), 30.5 (CH2CHCN) ppm. IR: νmax
= 2913, 2101, 1597, 1504, 1232, 747, 691 cm−1. HRMS (TOF MSES
positive mode) m/z calcd for C11H14N5 [MH]+: 216.1249, found
216.1243
4-Azido-4-(methyl(phenyl)amino)butanenitrile (40). Yield: 8 mg,
7%, not totally separated from 39, remaining as a 28% mixture with 40.
Oil. Rf: 0.55 (PE/EtOAc 75/25). 1H NMR (300 MHz, CDCl3): δ = 7.34
(t, 2H, Ph), 7.05−6.96 (m, 3H, Ph), 4.70 (dd, J = 8.5, 7.1 Hz, 1H,
CHCN), 3.58 (t, J = 6.1 Hz, 2H, CH2N3), 2.90 (s, 3H, Me), 2.26−2.03
(m, 2H, CH2CH2N3) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.2
(Cq), 129.5 (CAr), 121.6 (CAr), 117.4 (CAr), 117.1 (CHCN), 51.8
(CHCN), 47.0 (CH2N3), 34.5 (Me), 31.0. (CH2CH2N3) ppm. HRMS
(TOF MSES positive mode) m/z calcd for C11H14N5 [MH]+: 216.1249,
found 216.1249
Procedure for the Preparation of Ketone (41). Azetidine 26 (50
mg, 0.32 mmol) was dissolved in dry THF, and the solution was cooled
to 0 °C. A 2.5 M solution of BuLi in THF (252 μL, 0.64 mmol) was then
added dropwise. The mixture was stirred at 0 °C for 30 min and then
quenched with water. THF was removed under vacuum, and the
aqueous layer was extracted with EtOAc. The combined organic layers
were washed with brine and then dried over MgSO4. The residue was
then rapidly purified by flash chromatography on a short silica gel
column to provide 41 as a yellow oil.
1-(1-Phenylazetidin-2-yl)pentan-1-one (41). Yield: 49 mg, 71%.
Oil. Rf: 0.65 (PE/EtOAc 95/5). 1H NMR (300 MHz, CDCl3): δ = 7.24
(t, J = 8.0 Hz, 2H, Ph), 6.82 (t, J = 7.3 Hz, 1H, Ph), 6.44 (d, J = 8.2 Hz,
2H, Ph), 4.42 (t, J = 8.5 Hz, 1H, NCHCO), 4.08−3.94 (m, 1H, NCHH),
3.75 (q, J = 7.8 Hz, 1H, NCHH), 2.75 (dt, J = 17.5, 7.4 Hz, 1H,
COCHHCH2CH2Me), 2.65−2.35 (m, 3H, COCHHCH2CH2Me and
NCH2CH2), 1.64 (quint., J = 7.4 Hz, 2H, COCH2CH2CH2Me), 1.36
(sext., J = 7.4 Hz, 2H, COCH2CH2CH2Me), 0.93 (t, J = 7.3 Hz, 3H, Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 211.5 (CO), 150.8 (Cq), 129.0
J
DOI: 10.1021/acs.joc.6b00169
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The Journal of Organic Chemistry
Article
(CAr), 118.6 (CAr), 111.8 (CAr), 70.2 (NCHCO), 49.6 (NCH2), 37.2
(COCH2CH2CH2Me), 25.4 (COCH2CH2CH2 Me), 22.4
X-ray data for 33a (CIF)
X-ray data for 34a (CIF)
Computational details (PDF)
(COCH2CH2CH2Me), 21.7 (NCH2CH2), 13.9 (Me) ppm. IR: νmax
=
2955, 2926, 2866, 1707, 1598, 1499, 1328, 749, 691 cm−1. HRMS (TOF
MSES positive mode) m/z calcd for C14H20NO [MH]+: 218.1545,
found 218.1540
1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*Fax: +33 (0) 1 39 25 44 52. E-mail: couty@chimie.uvsq.fr.
Procedure for the Preparation of Alcohol 42. A solution of
ketone 41 (320 mg, 1.5 mmol) and ZnBr2 (364 mg, 1.6 mmol) in
MeOH (7 mL) was stirred at room temperature for 30 min. NaBH4 was
then added (84 mg, 2.2 mmol), and after 10 h of stirring at room
temperature, a further portion of NaBH4 was added (84 mg, 2.2 mmol)
to reach full conversion. Ethanolamine (350 μL, 5.9 mmol) was added,
and after 30 min of stirring the mixture was quenched with water and
extracted with EtOAc. The residue (de 88%) was purified by flash
chromatography to provide pure 42 as a clear oil.
(1S,2R)-1-(1-Phenylazetidin-2-yl)-pentan-1-ol (42). Yield: 200 mg,
63%. Oil. Rf: 0.6 (PE/EtOAc 95/5). 1H NMR (300 MHz, CDCl3): δ =
7.25 (t, J = 7.9 Hz, 2H, Ph), 6.84 (t, J = 7.3 Hz, 1H, Ph), 6.60 (d, J = 8.0
Hz, 2H, Ph), 4.11 (td, J = 7.9, 2.3 Hz, 1H, NCHCHOH), 4.05−3.97 (m,
1H, NCHCHOH), 3.94−3.84 (m, 1H, NCHH), 3.64 (q, J = 8.0 Hz, 1H,
NCHH), 2.95 (s, 1H, OH), 2.63−2.49 (m, 1H, NCH2CHH), 2.16−2.01
(m, 1H, NCH2CHH), 1.65−1.27 (m, 6H, COHCH2CH2CH2Me), 0.97
(t, J = 6.9 Hz, 3H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.2
(Cq), 129.0 (CAr), 118.7 (CAr), 112.5 (CAr), 70.4 (NCHCOH), 69.1
(NCHCOH), 50.1 (NCH2), 31.1 (COHCH2CH2CH2Me), 28.1
(COHCH2CH2CH2Me), 22.9 (COHCH2CH2CH2Me), 16.1
(NCH2CH2), 14.1 (Me) ppm. IR: νmax = 3455 (b), 2955, 2926, 2860,
1598, 1498, 1314, 750, 691 cm−1. HRMS (TOF MSES positive mode)
m/z calcd for C14H22NO [MH]+: 220.1701, found 220.1700
General Procedure for Suzuki Coupling. A solution of the
azetidine (2 mmol) in toluene (13 mL), a solution of phenylboronic acid
(488 mg, 4 mmol) in absolute EtOH (3 mL), and a 2 M aqueous
solution of Na2CO3 (3 mL) were stirred together while argon was
bubbled through the mixture for 15 min. Pd(PPh3)4 (36 mg, 5 mol %)
was then added, and the mixture was stirred at 90 °C under argon in a
sealed tube for 5 h, cooled to room temperature, and poured into EtOAc
and water. The aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine and then dried over MgSO4. The
residue was then purified by flash chromatography.
1-Biphenyl-4-yl-azetidine-2-carbonitrile (43). Yield: 430 mg, 91%.
White solid. Mp: 106−108 °C, Rf: 0.3 (PE/EtOAc 95/5). 1H NMR (300
MHz, CDCl3): δ = 7.60−7.50 (m, 4H, Ar), 7.43 (t, J = 7.5 Hz, 2H, Ar),
7.33 (d, J = 7.2 Hz, 1H, Ar), 6.68 (d, J = 8.7 Hz, 2H, Ar), 4.65 (dd, J = 8.4,
6.6 Hz, 1H, CHCN), 4.10 (ddd, J = 8.5, 6.8, 4.7 Hz, 1H, NCHH), 3.86
(dt, J = 8.3, 7.0 Hz, 1H, NCHH), 2.92−2.67 (m, 2H, NCH2CH2) ppm.
13C NMR (75 MHz, CDCl3): δ = 148.3 (Cq), 140.8 (Cq), 132.8 (CAr),
128.8 (CAr), 128.0 (CAr), 126.6 (CAr), 126.6 (CAr), 118.6 (CHCN),
112.4 (CAr), 50.6 (NCH2), 50.5 (CHCN), 22.5 (NCH2CH2) ppm. IR:
νmax = 3031, 2977, 2856, 1604, 1521, 1485, 1318, 1066, 826, 762, 690
cm−1. HRMS (TOF MSES positive mode) m/z calcd for C16H15N2
[MH]+: 235.1235, found 235.1230
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The University of Versailles St-Quentin-en-Yvelines and the
CNRS are acknowledged for funding. P.Q. acknowledges l’Ecole
polytechnique for a Ph.D. grant.
■
́
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