HFIP-mediated 2-aza-Cope rearrangement: Metal-free synthesis of α-substituted homoallylamines at ambient temperature

Article abstract of DOI:10.1039/d1ob00404b

An efficient metal-free strategy for the synthesis of α-substituted homoallylamine derivatives has been developed via a 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-promoted 2-aza-Cope rearrangement of aldimines, generated in situ by condensation of aldehydes with easily accessible 1,1-diphenylhomoallylamines. This reaction provides rapid access to α-substituted homoallylamines with excellent functional group tolerance and yields. The reaction takes place at room temperature and no chromatographic purification is required for product isolation. The synthetic utility of the current method is further demonstrated by the transformation of the obtained benzophenone ketimines into N-unprotected homoallylamines, an α-amino alcohol and an α-amino amide. This journal is

Full text of DOI:10.1039/d1ob00404b

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HFIP-mediated 2-aza-Cope rearrangement:
metal-free synthesis of α-substituted
homoallylamines at ambient temperature†
Cite this: Org. Biomol. Chem., 2021,
19, 4067
Karthik Gadde,
Bert U. W. Maes
and Kourosch Abbaspour Tehrani
*
An efficient metal-free strategy for the synthesis of α-substituted homoallylamine derivatives has been
developed via a 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-promoted 2-aza-Cope rearrangement of aldi-
mines, generated in situ by condensation of aldehydes with easily accessible 1,1-diphenylhomoallyla-
mines. This reaction provides rapid access to α-substituted homoallylamines with excellent functional
group tolerance and yields. The reaction takes place at room temperature and no chromatographic purifi-
cation is required for product isolation. The synthetic utility of the current method is further demonstrated
by the transformation of the obtained benzophenone ketimines into N-unprotected homoallylamines, an
α-amino alcohol and an α-amino amide.
Received 2nd March 2021,
Accepted 5th April 2021
DOI: 10.1039/d1ob00404b
rsc.li/obc
imines.15 Aldimines containing α-hydrogens often undergo
α-deprotonation with basic Grignard reagents. For this reason,
Introduction
Over the past decades, 1,1,1,3,3,3-hexafluoro-2-propanol less basic allylating reagents such as allyl stannanes, allyl
(HFIP) has flourished as a popular solvent in promoting silanes, allyl boronates and allyl boranes have been used for
chemical reactions1 including C–H activation reactions2 and the synthesis of α-substituted homoallylamines. However,
electrochemical transformations.3 HFIP has been used to these reagents are relatively expensive, exhibit major oper-
activate functional groups such as carbonyls,4 epoxides,5 ational safety issues and generate stoichiometric amounts of
alcohols,6 halides,7 sulfonates,8 phenols,3 nitrosoarenes,9 metal-containing (toxic) waste, which restrict their widespread
alkynes10 and alkenes.11 The widespread application of HFIP application. Furthermore, harsh deprotection conditions are
is due to its extreme properties, including its strong hydrogen- often required for the removal of the nitrogen protecting group
bond donating ability (α = 1.96), high ionizing power, high to obtain the more synthetically useful primary amines.
polarity (ε = 15.7), high oxidative stability, mild acidity (pKa = During this latter process, by-products are generated which
9.3), weak nucleophilicity, low viscosity, low boiling point often cannot be recovered and are consequently not reused for
(58 °C) and recyclability.1,2 The current report discusses an reagent synthesis.
HFIP promoted imine activation reaction to access scarcely
available α-substituted homoallylamines under metal-free cationic 2-aza-Cope rearrangement of ene-imines.16 Pioneering
conditions.1,12
studies from Overman and co-workers showed extensive appli-
In 1950, Horowitz and Geissman were the first to report a
Substituted homoallylamines are privileged precursors for cations of cationic 2-aza-Cope rearrangement in combination
the preparation of nitrogen-containing natural products and with a Mannich reaction for alkaloid syntheses.17 However, the
heterocycles in synthetic organic chemistry and the pharma- 2-aza-Cope rearrangement strategy has rarely been used for the
ceutical and agrochemical industries.13 The most commonly synthesis of α-substituted homoallylamines.18–22 There are
used method to prepare α-substituted homoallylamines only a limited number of protocols in the literature using alde-
is the direct nucleophilic addition of allylic organometallic hydes for the synthesis of chiral α-substituted homoallylamine
reagents to aldimines (Fig. 1A).14 However, the addition of by means of a 2-aza-Cope rearrangement strategy involving
Grignard reagents to aldimines is limited to non-enolizable either chiral amine precursors18 or chiral catalysts19 (Fig. 1B).
We recently reported that iron(III) chloride can be used as a
Lewis acid catalyst at 90 °C in dimethyl carbonate to trigger
the 2-aza-Cope rearrangement for the synthesis of
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171,
α-substituted homoallylamines.20 Most recently, Yang and co-
B-2020 Antwerp, Belgium. E-mail: kourosch.abbaspourtehrani@uantwerpen.be
workers reported a bismuth(III)-catalyzed 2-aza-Cope rearrange-
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
ment method for β-aminophosphonate synthesis from
d1ob00404b
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Fig. 1 Synthesis of α-substituted homoallylamines.
Scheme 1 (A) Working hypothesis. (B) Preparation of the starting
materials.
α-phosphoryl aldehydes and 1,1-diphenylhomoallylamines at
100 °C in 1,2-dichloroethane under an argon atmosphere.21
Despite the significant advantages of the 2-aza-Cope rearrange-
ment method for the synthesis of α-substituted homoallyla-
mines, unfortunately, all of these methods still show some
limitations, including the use of a (metal) catalyst, elevated
temperature, inert atmosphere and low yields. Therefore,
further exploration of new mild and generally applicable
methods to access α-substituted homoallylamines is still
highly desirable. To overcome the abovementioned limitations
and in continuation of our interest in imine activation
reactions,12,23 we hypothesized that HFIP could be effective to
promote the 2-aza-Cope rearrangement of aldimines to access
α-substituted homoallylamines starting from commercially
available aldehydes and easily accessible 1,1-diphenylhomo-
allylamines at room temperature under metal-free conditions
(Fig. 1C). We envisioned that aldimine 3 would be formed first
workup the more synthetically useful N-unprotected
α-substituted homoallylamines 5 could be obtained. Based on
previous knowledge,19–22 we noticed that the choice of 1,1-
diphenylhomoallylamine 2 was crucial for generating the steri-
cally congested aldimine 3, which favours the 2-aza-Cope
rearrangement of 3 to the more stable ketimine 4 through a
cyclic transition state mediated by either a Lewis acid or a
Brønsted acid. The required 1,1-diphenylhomoallylamines 2
can be easily prepared on a gram scale from benzophenone
imines and allylmagnesium chlorides and could be easily puri-
fied via acid–base extraction without using any chromato-
graphic technique (Scheme 1B).19
Results and discussion
by condensation of aldehyde 1 and 1,1-diphenylhomoallyla- To verify our hypothesis, we commenced test reactions in HFIP
mine 2. Subsequently, the strong hydrogen-bond donating by using benzaldehyde (1a) and 1,1-diphenylbut-3-en-1-amine
ability and mild acidity of HFIP would promote the aldimine (2a) as model substrates, and the results are presented in
to undergo a 2-aza-Cope rearrangement to give the corres- Table 1. We were delighted to observe the formation of the tar-
ponding rearranged ketimine 4 (Scheme 1A). Furthermore, the geted product 4a in 99% yield by using an equimolar mixture
obtained rearranged imine 4 could be easily hydrolyzed under of 1a and 2a in HFIP in the presence of 4 Å molecular sieves at
mild acidic conditions, and by means of a simple acid–base room temperature (Table 1, entry 1). It is important to
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Table 1 Evaluation of various reaction parameters for the synthesis of 4a
parable yield in HFIP (pKa = 9.3). The comparatively less acidic
fluorinated alcohol TFE (pKa = 12.4) led to no detectable
product 4a and furnished 3a in a quantitative yield (entry 9).
Replacing HFIP with its non-fluorinated analogue isopropanol
(pKa = 16.5) did not yield the desired product 4a, showing that
the hydrogen bonding network and hydrogen bond donating
ability of HFIP are crucial for the success of the 2-aza-Cope
rearrangement step (entry 10). The use of an alternative acidic
solvent, acetic acid (pKa = 4.76), was found to be inferior and
led to a significantly reduced yield of 4a, probably due to the
fact that acetic acid is an inferior hydrogen bond donor com-
pared to HFIP (entry 11).24 Omitting the 4 Å molecular sieves
was not beneficial for the yield of 4a and led to incomplete
conversion of the starting material and hydrolysis of 4a
(entry 12). Solvent screening studies revealed that either HFIP
or a combination of HFIP with toluene or DCM was the best
choice of solvent in terms of delivering near-quantitative yields
of 4a. Eventually, HFIP was selected as the sole solvent for the
substrate scope study.
With the optimized reaction conditions in hand (Table 1,
entry 1), we next investigated the generality of this method-
ology on a range of aldehydes 1 with 1,1-diphenylhomoallyla-
mines 2. As shown in Scheme 2, a broad range of aldehydes
having various functional groups were well tolerated under the
reaction conditions and furnished the desired products in
excellent yields. The reaction of homoallylamine 2a with
p-tolualdehyde (1b), p-anisaldehyde (1c), o-anisaldehyde (1d),
m-anisaldehyde (1e), 3,5-dimethoxybenzaldehyde (1f), p-(tri-
fluoromethyl)benzaldehyde (1g) and 2-naphthaldehyde (1h)
delivered the products 4b–h in 99%, 94%, 95%, 98%, 80%,
96% and 80% yields, respectively. The reaction with haloge-
nated benzaldehydes, p-fluorobenzaldehyde (1i), p-chloroben-
zaldehyde (1j), p-bromobenzaldehyde (1k), o-bromobenzalde-
hyde (1l) and m-bromobenzaldehyde (1m), afforded the corres-
ponding homoallylamines 4i–m in near-quantitative yields.
Gratifyingly, a broad range of functional groups, including
nitro (1n–p), nitrile (1q), ester (1r), ketone (1s) and alkyne (1t),
were well tolerated under the reaction conditions, furnishing
the corresponding homoallylamines 4n–t in excellent yields. It
is important to note that the reaction of benzaldehydes
bearing electron-donating groups (–Me, –OMe) at the ortho-
Yielda
(%)
Entry
Solvent
HFIP (equiv.)
Time (h)
3a
4a
1
2
3
4
5
6
7
8
HFIP
9.5
5.0
5.0
5.0
5.0
3
0
99
0
0
99
99
0
0
95
0
0
68
38
HFIP/THF (1 : 1)
HFIP/MeCN (1 : 1)
HFIP/toluene (1 : 1)
HFIP/DCM (1 : 1)
Toluene
DCM
PFTB
TFE
i-PrOH
AcOH
HFIP
12
12
12
12
12
12
12
12
12
12
12
99
99
0
0
99
99
5
99
99
9
9
10
11
12b
0
Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (0.5 mmol, 1.0
equiv.), 4 Å MS (200 mg), solvent (0.5 mL), air, room temperature. a 1H
NMR yields were determined by means of 1,3,5-trimethoxybenzene as
the internal standard. b The reaction was performed without 4 Å MS.
MS = molecular sieves. HFIP = 1,1,1,3,3,3-hexafluoro-2-propanol. THF
= tetrahydrofuran. DCM = dichloromethane. PFTB = perfluoro-tert-
butyl alcohol. TFE = 2,2,2-trifluoroethanol.
mention that no extra catalyst was used for this reaction. Next, and para-positions required longer reaction time than that of
HFIP was employed as an additive in combination with sol- benzaldehydes bearing electron-withdrawing groups (–F, –Cl,
vents such as tetrahydrofuran (THF), acetonitrile, toluene and –Br, –NO2, –CN, –CO2Me, –CF3). Importantly, the substrate
dichloromethane (DCM) (entries 2–5). As expected, the use of scope study with respect to heteroatom-containing aromatic
hydrogen bond acceptor co-solvents, THF and acetonitrile, did aldehydes such as pyridinecarboxaldehydes (1u–w), 4-quinoline-
not yield the desired product 4a, but rather delivered aldimine carboxaldehyde (1x), 1-methyl-1H-pyrazole-4-carboxaldehyde
3a exclusively (entries 2 and 3). On the other hand, the use of (1y) and 2-thiophenecarboxaldehyde (1z) furnished the pro-
poor hydrogen bonding co-solvents, toluene and DCM, yielded ducts 4t–z in yields ranging from 80% to 99%, highlighting
the desired product 4a exclusively (entries 4 and 5). When the the expediency of this protocol. Moreover, aliphatic aldehydes
reaction was performed in pure toluene or DCM, in the also proved to be efficient substrates in this transformation
absence of HFIP, only the non-rearranged aldimine 3a was iso- and afforded the corresponding homoallylamines 4aa–ah in
lated (entries 6 and 7). Other fluorinated solvents such as good to excellent yields. We next extended the scope of the
2,2,2-trifluoroethanol (TFE) and perfluoro-tert-butanol (PFTB) reaction with respect to the amine partner, using 2-methyl-1-
were subsequently evaluated (entries 8 and 9). Among them, 1-diphenylbut-3-en-1-amine (2b). The selected aldehydes with
PFTB (pKa = 5.2) gave the desired product 4a (95%) in a com- 2b furnished the corresponding homoallylamines 4ai–an in
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Scheme 2 Substrate scope of HFIP-promoted 2-aza-Cope rearrangement.
good to excellent yields. It is noteworthy that none of the
Subsequently, in order to validate our hypothesis, we
examples in Scheme 2 required column chromatographic carried out a few control experiments (Scheme 3) and systema-
1
purification.
tic H NMR experiments as shown in Fig. 2. First, we prepared
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aldimine 3a by using benzaldehyde (1a) and 1,1-diphenylbut-
3-en-1-amine (2a) in 2,2,2-trifluoroethanol (Scheme 3A). Then,
aldimine 3a was used as the starting material applying
standard reaction conditions in the absence of 4 Å molecular
sieves to obtain 4a in a quantitative yield (Scheme 3B). These
experiments implied that aldimine 3a was an intermediate
and that the use of HFIP was necessary for the 2-aza-Cope
rearrangement step under standard reaction conditions.
To further showcase the role of HFIP, the 1H NMR spectrum
was recorded immediately after mixing aldimine 3a and HFIP
(1.3 equiv.) in deuterated chloroform at room temperature
(Fig. 2C). Clear shifts of the aldimine proton peak (from
7.82 ppm to 7.88 ppm), the OH peak of HFIP (from 2.94 ppm
to 3.94 ppm) and the CH peak of HFIP (from 4.40 ppm to
4.10 ppm) were observed. These observations clearly indicated
the H-bond interaction between aldimine 3a and HFIP,
showing that aldimine 3a was activated by hydrogen bonding
interactions with HFIP towards the product 4a.12c
Scheme 3 Control experiments.
A gram-scale experiment was performed for showcasing the
scalability of this method (Scheme 4A). A 5 mmol scale reac-
tion between benzaldehyde (1a) and 1,1-diphenylbut-3-en-1-
amine (2a) was carried out in HFIP (5 mL) at room tempera-
Fig. 2 Stacked 1H NMR (400 MHz, CDCl3) spectra of (A) aldimine 3a, (B) HFIP, (C) a 1 : 1.3 mixture of aldimine 3a and HFIP (0.25 mmol), (D) the reac-
tion mixture (0.25 mmol, 30 min later), and (E) product 4a. In spectrum (C), the pink star indicates the position of the deshielded aldimine proton
peak and the green square indicates the position of the deshielded O–H peak of HFIP.
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ture, furnishing the desired product 4a in 91% yield and HFIP
(4.1 mL) was recovered after distillation using a Kugelrohr
apparatus. Furthermore, 4a was easily hydrolyzed under mild
acidic conditions which delivered primary α-substituted homo-
allylamine 5a in 89% yield and benzophenone (6) in 90% yield
after simple acid–base extraction. Importantly, the recovered
benzophenone can be reused for the synthesis of substrate
2a.25 Furthermore, the recovered HFIP was reused in a sub-
sequent reaction between 1a and 2a to afford 4a in 92% yield
(Scheme 4B).
To further illustrate the utility of our methodology, a direct
diversification to
a renewable aldehyde was attempted.
5-Hydroxymethylfurfural (1ao) was selected as a model bio-
platform molecule as it features the carbonyl group, the
hydroxy group, and the furan ring. The reaction of 1ao with 2a
under the optimal reaction conditions delivered the target
product 4ao in 88% yield (Scheme 4C). Next, a two-step, one-
pot synthesis of N-benzhydryl-protected primary amine 7 was
achieved from benzaldehyde (1a) and 1,1-diphenylbut-3-en-1-
amine (2a). The HFIP-promoted 2-aza-Cope rearrangement of
aldimine and the subsequent reduction (same pot) of ketimine
with sodium cyanoborohydride led to
7 in 95% yield
(Scheme 4D). The synthetic utility of the reaction was further
highlighted by post-synthetic modification of a homoallyla-
mine derivative 4aa towards the synthesis of α-amino alcohol 8
and α-amino amide 10 via visible-light-mediated cross-coup-
ling reactions using benzaldehyde (1a) and benzyl isocyanate
(9) as electrophiles respectively (Scheme 4E).26,27 One-step con-
version of the homoallylamine derivative 4aa into α-amino
alcohol 8 was achieved in 68% yield (Scheme 4E, eqn (1)).26
The synthesis of α-amino amide 10 was achieved in 54% yield
from the reaction of homoallylamine derivative 4aa with
benzyl isocyanate (9) (Scheme 4E, eqn (2)).27
Conclusions
We herein developed an efficient and robust HFIP-promoted
2-aza-Cope rearrangement reaction leading to the formation
of a broad range of α-substituted homoallylamines from
commercially available aldehydes and easily synthesizable
1,1-diphenylhomoallylamines. This method allows rapid
access to α-substituted homoallylamines under mild con-
ditions in good to excellent yields with excellent functional
group tolerance and water as the sole by-product. Notably,
the method is metal-free and works for both aliphatic and
(hetero)aromatic aldehyde substrates; the reactions operate at
ambient temperature under an open-air atmosphere and
without the requirement of chromatographic purification for
product isolation. Furthermore, the obtained products (ben-
zophenone ketimines) are easily hydrolyzed under mild
acidic conditions to obtain the more synthetically useful
N-unprotected α-substituted homoallylamines. Post-synthetic
modification of ketimines into an α-amino alcohol and an
α-amino amide demonstrated the further synthetic utility of
this method.
Scheme 4 Scalability and synthetic utility of the developed method. (A)
Gram-scale experiment and hydrolysis of ketimine 4a. (B) Recycling
study of HFIP. (C) Diversification of 5-hydroxymethylfurfural. (D)
Synthesis of N-benzhydryl protected homoallylamine 7. (E) The syn-
thetic transformation of 4aa into α-amino alcohol
amide 10.
8 and α-amino
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apparatus to obtain pure 1,1-diphenyl-N-(1-phenylbut-3-en-1-
yl) methanimine (4a) in 91% yield and HFIP (4.1 mL) was
recovered.
Experimental section
General information
All aldehydes used were purchased from commercial sources
and used as received. The starting materials, 1,1-diphenylbut-
3-en-1-amine (2a) and 2-methyl-1,1-diphenylbut-3-en-1-amine
Procedure for the hydrolysis of 4a and recovery of
benzophenone
(2b), were prepared using known literature procedures.19 4 Å In a 100 mL round bottom flask, 4a (1.417 g, 4.55 mmol) was
molecular sieves (powder) were purchased from Sigma-Aldrich dissolved in 2-MeTHF (20 mL), followed by the addition of 2 N
and activated prior to use by drying in a vacuum oven at aqueous HCl solution (10 mL). The reaction mixture was then
200 °C for 24 h. HFIP was purchased from Fluorochem and stirred for 5 h at room temperature and monitored by TLC.
used as received. All reactions were carried out in oven-dried Upon completion of the reaction, 2-MeTHF was removed
vials. Nuclear magnetic resonance (NMR) spectra were under reduced pressure and 10 mL of H2O was added. The
recorded on a Bruker Model Avance 400 Fourier transform mixture was washed with EtOAc (4 × 5 mL) and the combined
NMR spectrometer in CDCl3 at room temperature (unless organic phase was extracted with water (5 mL) and then
stated otherwise). All spectra were referenced to the TMS peak washed with EtOAc (1 mL). The ethyl acetate fractions were
(δ = 0.00 ppm for both 1H NMR and 13C NMR in CDCl3). High- combined and dried using MgSO4, following which the solvent
resolution mass spectrometry (HRMS) samples were prepared was removed under reduced pressure to afford pure benzophe-
by dissolving 0.1–3.0 mg of compound in MeCN and further none (6, 0.746 g, 90%). The previous combined aqueous phase
diluting to a concentration of 10−5–10−6 M with 50% MeCN/ was neutralized with 3 N aqueous NaOH solution and
50% H2O. The samples were injected in the MS system using a extracted with ethyl acetate; the organic fractions were com-
CapLC system (Waters) and a nanoelectrospray source operated bined and dried using MgSO4, following which the solvent was
in the positive ion mode at a potential of 1.5 or 1.7 kV. The removed under reduced pressure to afford pure 1-phenylbut-3-
eluent used was 30% A (0.1% formic acid in H2O) and 70% B en-1-amine (5a, 0.596 g, 89%).
(0.1% formic acid in MeCN/H2O-95/5) at a flow rate of 6.0 mL
Procedure for the synthesis of 4ao from
5-hydroxymethylfurfural
min−1. Samples were injected with an interval of 3 min. Before
analysis, 2.0 mL of a 0.025% H3PO4 solution (MeOH/H2O-50/
50) or 10.0 mL of 10−6 M deoxyadenosine solution (MeOH/ In an oven-dried 10 mL vial, 1,1-diphenylbut-3-en-1-amine (2a)
H2O-50/50) was injected as a lock mass. Positive-ion mode (112 mg, 0.5 mmol, 1.0 equiv.), 5-hydroxymethylfurfural (1ao)
accurate mass spectra were acquired using a Q-TOF instru- (63 mg, 0.5 mmol, 1.0 equiv.), 4 Å molecular sieves (200 mg)
ment. Melting points were measured on a Buchi B-545 capil- and HFIP (0.5 mL) were added successively, and the vial was
lary melting point apparatus. Full characterization data and capped under air. The reaction mixture was then vigorously
NMR spectra for all compounds are provided in the ESI.†
stirred for 6 h at room temperature. After the reaction time,
the reaction mixture was filtered and the solvent was removed
under reduced pressure to afford the desired product 4ao
(0.146 g, 88%).
General procedure for the synthesis of α-substituted
homoallylamines 4
In an oven-dried 10 mL vial, 1,1-diphenylbut-3-en-1-amine (2a
or 2b) (0.5 mmol, 1.0 equiv.), aldehyde 1 (0.5 mmol, 1.0
equiv.), 4 Å molecular sieves (200 mg) and HFIP (0.5 mL, 9.5
Procedure for the synthesis of N-benzhydryl-protected
homoallylamine 7
equiv.) were added successively, and the vial was capped under In an oven-dried 10 mL vial, 1,1-diphenylbut-3-en-1-amine (2a)
air. The reaction mixture was then vigorously stirred for the (0.5 mmol, 1.0 equiv.), benzaldehyde (1a) (0.5 mmol, 1.0
indicated time (see Scheme 2) at room temperature. After the equiv.), 4 Å molecular sieves (200 mg) and HFIP (1.0 mL) were
reaction time, the reaction mixture was filtered and the solvent added successively, and the vial was capped under air. The
was removed under reduced pressure to afford pure reaction mixture was then stirred for 6 hours at room tempera-
α-substituted homoallylamine derivatives 4 (see Scheme 2 for ture. After 6 hours, sodium cyanoborohydride (126 mg, 4.0
yields and the ESI† for the detailed experimental procedure, equiv.) was added to the reaction mixture. Then, the reaction
characterization data and NMR spectra).
vial was flushed with argon for 5 minutes and then the vial
was sealed with a septum. The reaction vial was stirred at
room temperature under argon for 6 hours. After the reaction
Procedure for the gram-scale synthesis of 4a
In an oven-dried 25 mL vial, 1,1-diphenylbut-3-en-1-amine (2a) time, the reaction mixture was filtered, and the solvent was
(1.117 g, 5.0 mmol, 1.0 equiv.), benzaldehyde (1a) (0.531 g, removed under reduced pressure. Then the reaction mixture
5.0 mmol, 1.0 equiv.), 4 Å molecular sieves (2 g) and HFIP was diluted with DCM and washed with 1 N aqueous NaOH
(5 mL) were added successively, and the vial was capped under solution. The aqueous layer was extracted with DCM. The com-
air. The reaction mixture was then vigorously stirred for 12 h at bined DCM layers were dried using MgSO4 and concentrated
room temperature. After the reaction time, the reaction in vacuo. The crude residue was purified with an automated
mixture was filtered and HFIP was distilled off under reduced flash chromatography system on silica gel using an n-heptane/
pressure at room temperature with a Kugelrohr distillation EtOAc gradient (from 100% n-heptane to 10% EtOAc in
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25 minutes, 25 mL min−1). N-Benzhydryl-1-phenylbut-3-en-1-
amine (7) was obtained in 95% (149 mg) yield.
Notes and references
1 For reviews on
HFIP, see: (a)
I. Colomer,
Procedure for the synthesis of α-amino alcohol 8 from 4aa
A. E. R. Chamberlain, M. B. Haughey and T. J. Donohoe,
Nat. Rev. Chem., 2017, 1, 0088; (b) V. Pozhydaiev, M. Power,
V. Gandon, J. Moran and D. Leboeuf, Chem. Commun.,
2020, 56, 11548–11564; (c) J.-P. Bégué, D. Bonnet-Delpon
and B. Crousse, Synlett, 2004, 18–29; (d) I. A. Shuklov,
N. V. Dubrovina and A. Börner, Synthesis, 2007, 2925–2943.
2 (a) T. Bhattacharya, A. Ghosh and D. Maiti, Chem. Sci.,
2021, 12, 3857–3870; (b) S. K. Sinha, T. Bhattacharya and
D. Maiti, React. Chem. Eng., 2019, 4, 244–253; (c) J. Wencel-
Delord and F. Colobert, Org. Chem. Front., 2016, 3, 394–
400.
This experimental procedure was adapted from a literature
procedure.26 In an oven-dried 4 mL Wheaton vial, N-(but-3-en-
1-yl)-1,1-diphenylmethanimine (4aa) (24 mg, 0.1 mmol, 1.0
equiv.), [Ir(ppy)2(4,4′-tBu-bpy)] PF6 (0.5 mg, 0.5 mol%), methyl-
dicyclohexylamine (39 mg, 0.2 mmol, 2.0 equiv.), benz-
aldehyde (1a) (13 mg, 0.120 mmol, 1.2 equiv.) and anhydrous
MeCN (1 mL) were added successively. The reaction vial was
flushed with argon for 5 minutes, and then the vial was sealed
with a septum. The reaction mixture was placed under a 19 W
blue LED light source and stirred at ambient temperature
(∼30 °C) for 20 h. After 20 h, the vial was opened to air and the
volatile materials were removed using a rotary evaporator
under reduced pressure. The crude residue was purified with
an automated flash chromatography system on silica gel using
an n-heptane/EtOAc gradient (from 100% n-heptane to 10%
EtOAc in 25 minutes, 25 mL min−1). 2-(But-3-en-1-ylamino)-
1,2,2-triphenylethan-1-ol (8) was obtained in 68% (23 mg)
yield.
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This experimental procedure was adapted from a literature
procedure.27 In an oven-dried 4 mL Wheaton vial, N-(but-3-en-
1-yl)-1,1-diphenylmethanimine (4aa) (24 mg, 0.1 mmol, 1.0
equiv.), [Ir(ppy)2(4,4′-tBu-bpy)] PF6 (1 mg, 1.0 mol%), methyl-
dicyclohexylamine (39 mg, 0.2 mmol, 2 equiv.), benzyl isocya-
nate (9) (27 mg, 0.2 mmol, 2 equiv.) and anhydrous MeCN
(1 mL) were added successively. The reaction vial was flushed
with argon for 5 minutes and then the vial was sealed with a
septum. The reaction mixture was placed under a 19 W blue
LED light source and stirred at ambient temperature (∼30 °C)
for 20 h. After 20 h, the vial was opened to air and the volatile
materials were removed using a rotary evaporator under
reduced pressure. The crude residue was purified with an auto-
mated flash chromatography system on silica gel using an
n-heptane/EtOAc gradient (from 100% n-heptane to 10%
EtOAc in 25 minutes, 25 mL min−1). N-Benzyl-2-(but-3-en-1-
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(20 mg) yield.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was financially supported by the University of
Antwerp (BOF) and the Hercules Foundation. The authors are 13 For representative examples, see: (a) C. O. Puentes and
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