Accessing α-Arylated Nitriles via BF3·OEt2 Catalyzed Cyanation of para-Quinone Methides Using tert-Butyl Isocyanide as a Cyanide Source

Article abstract of DOI:10.1021/acs.joc.8b01926

BF₃·OEt₂ catalyzed 1,6-conjugate addition of tert-butyl isocyanide to para-quinone methides and fuchsones for the synthesis of α-diaryl and α-triaryl nitriles has been reported. This protocol allows α-diaryl- and α-triaryl nitriles to be accessed in good to excellent yields and with a broad substrate scope, which could be further functionalized to give a versatile set of products. This is the first example wherein tert-butyl isocyanide has been used as a cyanide source for the 1,6-conjugate addition.

Full text of DOI:10.1021/acs.joc.8b01926

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Note
Accessing #-arylated Nitriles via BF3.OEt2 Catalyzed Cyanation of para-
Quinone Methides using tert-Butyl Isocyanide as a Cyanide Source
Sachin R. Shirsath, Ganesh H. Shinde, ASLAM CHANDBHAI SHAIKH, and M Muthukrishnan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01926 • Publication Date (Web): 11 Sep 2018
Downloaded from http://pubs.acs.org on September 11, 2018
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Accessing α-arylated Nitriles via BF3.OEt2 Catalyzed Cyanation of
para-Quinone Methides using tert-Butyl Isocyanide as a Cyanide
Source
Sachin R. Shirsath,a,b Ganesh H. Shinde,a Aslam C. Shaikha and M. Muthukrishnan*a,b
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aDivision of Organic Chemistry, CSIR-National Chemical Laboratory, Pune 411008, India
bAcademy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
ABSTRACT: BF3.OEt2 catalyzed 1,6-conjugate addition of tert-butyl isocyanide to para-
quinone methides and fuchsones for the synthesis of α-diaryl- and α-triaryl nitriles has been
reported. This protocol allows to access α-diaryl- and α-triaryl nitriles in good to excellent
yields and with a broad substrate scope, which could be further functionalized to give a
versatile set of products. This is the first example wherein tert-butyl isocyanide has been used
as a cyanide source for the 1,6-conjugate addition.
The synthesis of nitrile containing organic frameworks, in particular α-arylated nitrile
compounds is of great importance as these structures exist in several natural products,
a vast range of functional molecules relevant to pharmaceuticals, agrochemicals and
functional materials (Figure 1).1 For instance, more than 30 nitrile-containing drugs
have been approved for the treatment of depression, breast cancer, and Parkinson’s
disease, while 20 more are in clinical trials.2 On the other hand, they are valuable
precursors in organic synthesis for the preparation of carboxylic acids, amides,
aldehydes, ketones, amidines, amines,
N
-containing heterocycles, etc.3 or as directing
−H activation through weak coordination.4
groups for remote C
Consequently, several
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synthetic approaches towards the synthesis of
α
-arylated nitriles have been explored
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and that mainly involves nucleophilic substitution of a benzylic halide,5 dehydration of
aldoximes/amides,6 addition of cyanide to diarylcarbinols,7 coupling reactions of
nitriles with aryl halides,8 and others.9 However, most of these methods suffer from
drawbacks such as harsh reaction conditions, expensive catalysts and usage of
notorious toxic cyanide sources etc. Therefore, the development of robust strategy
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aiming the synthesis of diverse functional group rich α-aryl-nitriles is highly desirable.
Figure 1. Representative biologically important α-arylated nitriles.
In recent years, the
p-quinone methides (p-QMs) have attracted a great deal of
attention among synthetic community due to its unique reactivity and its ability to
make complex architecture that are found in several pharmaceuticals and natural
products.10 The
mainly 1,6-conjugate additions,11 [4 + 2]-annulations,12 [3 + 2]-annulations,13 and [2
+1]-annulations.14 Very recently,
p-QMs has the ability to undergo several reaction modes that involves
p
-QMs have been successfully utilized for the
synthesis of α-diaryl- and α-triaryl nitriles wherein the reaction relied upon the usage
of TMSCN as a cyanide source and NHC-catalyst for the activation of TMSCN.15 As
part of our continuing interest in the synthesis of natural product like small molecules
for various biological applications,16 we encountered a need for an efficient
methodology for the synthesis of α-arylated nitriles. With regard to practicality, we
chose to explore tert-butyl isocyanide as an alternate cyanide source, avoiding the use
-QM. 17 Importantly, in recent
of toxic cyanides for 1,6 conjugate addition reaction of
p
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years tert-butyl isocyanide has been efficiently utilized as alternative "CN" source.18
Hence, in the present manuscript we describe the amenability of tert-butyl isocyanide
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as a source of cyanide for the successful preparation of
from -QMs. To the best of our knowledge, this is the first example where tert-butyl
isocyanide has been used as a cyanide source for the 1,6-conjugate addition.
We began our optimization studies with -quinone methide 1a, which contains
removable -Bu groups at the ortho positions and tert-butyl isocyanide as a source
of cyanide under variable reaction conditions (Table 1). An initial experiment was
conducted with 1a and in the presence of 20 mol% Sc(OTf)3 as a catalyst in CH2Cl2
α-diaryl- and α-triaryl nitriles
p
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p
t
2
2
solvent at room temperature. Gratifyingly, the desired product 3a was isolated in 36%
yield after 30 mins (Table 1 entry 1). Encouraged by this initial result, we next
screened various Lewis acid catalysts, such as Bi(OTf)3, BF3.(OEt)2, Yb(OTf)3, TiCl4,
InCl3 and Cu(OTf)2 (Table 1, entries 2-7) to define the best catalyst for this
transformation. Among the above Lewis acid catalysts examined, BF3.(OEt)2 was
found to be the most effective one to give the desired product 3a in 64% yield (Table 1
entry 3). The reaction conditions were further optimized by varying solvents such as
THF, Et2O, CH3CN, & DMSO and the results revealed that CH2Cl2 was superior to
other solvents. (Table 1, entry 3 vs entries 8-11). Interestingly, increasing the
t
equivalents of BuNC to 1.3 equiv., the desired product formation was observed in
76% yield (Table 1, entry 12). Next, we examined the effect of catalyst loading and it
was observed that 25 mol% of BF3.(OEt)2 appears ideal for this reaction as it provides
the desired product in 90% yield (Table 1, entry 12-14). Further, increasing catalyst
t
loading as well as variation in stoichiometric quantity of BuNC did not have much
impact in the reaction efficiency (Table 1, entry 15,16). No product was detected when
the reaction was performed without the catalyst (Table 1, entry 17).
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Table 1. Optimization of reaction conditions.a,
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Entry
Cat.
tBu-NC
(equiv)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.3
1.3
1.3
Solvent
Yield (%)
3a
36
42
64
<10
14
trace
32
trace
27
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Sc(OTf)3
Bi(OTf)3
BF3.OEt2
Yb(OTf)3
TiCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
InCl3
Cu(OTf)2
BF3.OEt2
BF3.OEt2
BF3.OEt2
BF3.OEt2
BF3.OEt2
BF3.OEt2
BF3.OEt2
BF3.OEt2
BF3.OEt2
--
Et2O
CH3CN
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
41
n.r.
76
59b
90c
88d
92c
n.r.e
1.5
1.3
t
aPerformed with
p
-QMs 1a (0.1 mmol), BuNC
room temperature. 10 mol% of BF3.OEt2 was used, 25 mol% of BF3.OEt2 was used, d30 mol% of BF3.OEt2 was
2
(0.1 mmol) and 20 mol % of Lewis acid in solvent (1 mL) at
c
b
e
used Without catalyst.
With the optimized reaction conditions in hand, we next explored the scope of
the reaction with respect to
to find that a broad range of
furnish the corresponding products in 48
p
-quinone methides (
-QMs underwent reaction with tert-butyl isocyanide to
−97% yield
p-QMs) (Table 2). We were pleased
p
s. Both electron-donating (R = -
Me, -OMe, -NMe2) and electron-withdrawing groups (R = -CN, -NO2) at the para,
ortho or meta positions of the benzene rings were well tolerated, offering the desired
products in good to excellent yields (3a
−3p). The halo-substituted p-QMs also well
tolerated to yield the desired product in moderate to good yields. Furthermore, di-
substitution on the benzene ring of
p
-QMs were also found to be suitable substrates
and the corresponding products (3q
–
3s) were isolated under the optimal conditions.
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Interestingly,
p
-QM (1t) derived from the chromone-3-carboxaldehyde, also works
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well to results the desired cyano-addition product 3t in 48% yield. Heterocyclic
substituted -QMs, like furan and thiophene, were also amenable to this protocoland
generates the corresponding cyano products in good yields (65 & 77%, 3u 3v).
However, pyridyl ring bearing -QM was failed to afford the desired product (3w).
Notably, the sterically hindered naphthyl, anthracenyl, fluorenyl, and biphenyl
substitution bearing -QMs were also susceptible in this process to furnish the desired
p
9
-
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p
p
cyano-product (3x-3aa) in good yields (79-84%). It is noteworthy to mention here
that,
Table 2. Substrate scope of the reactiona
O
OH
tBu
Ar
tBu
tBu
Ar
tBu
tBu-NC (2)
BF3.OEt2 (25 mol%)
CH2Cl2, rt
CN
3
1
OH
OH
tBu
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
tBu
R
R
CN
CN
CN
CN
Cl
Cl
R
3q, 1 h, 63%
, R = OMe, 0.5 h, 79%
3n, R = Br, 35 min, 75%
3m
3o, R = Cl, 0.5 h, 70%
3p, R = F, 0.5 h, 66%
, R = H, 0.5 h, 90%
3a
3b, R = Me, 0.5 h, 85%
3c, R = iPr, 20 min, 78%
OH
tBu
OH
OH
3d, R = tBu, 45 min, 72%
3e, R = OMe, 45 min, 89%
3f, R = OBn, 20 min, 97%
3g, R = NMe2, 0.5 h, 96%
3h, R = Cl,, 20 min,78%
3i, R = Br, 20 min,81%
, R = CF , 1 h, 70%
tBu
tBu
tBu
tBu
tBu
O
F
MeO
MeO
CN
CN
CN
O
Br
3j
3
, 25 min, 52%
3s
3t, 0.5 h, 48%
, 15 min, 98%
3r
, R = CN, 3 h, 59%
3k
, R = NO , 1.5 h, 64%
3l
2
OH
OH
tBu
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
CN
CN
CN
CN
3u, 0.5 h, 77%
CN
N
S
O
3x, 1 h, 80%
3v, 0.5 h, 65%
, --%b
3w
3y, 1 h, 79%
OH
OH
OH
tBu
tBu
tBu
OH
iPr
tBu
tBu
tBu
iPr
CN
CN
CN
CN
Ph
3z, 20 min, 84%
Ph
3ab, 25 min, 80%
, 0.5 h, 82%
3aa
3ac, 45 min, 78%
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t
aPerformed with
p
-QMs
1
(0.1 mmol) Bu-NC
2
(0.13 mmol) and BF3.OEt2 (25 mol%) in CH2Cl2 (1 mL) at room
temperature. bNo desired product formation.
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alkyne group tethered p-QM was also well tolerated under optimized reaction condition to
afford the desired product (3ab) in good yield (80%). Additionally, p-QM (1ac) bearing two
isopropyl groups at the ortho position was also well tolerated, to afford the product 3ac in
78% yield.
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Next, we examined the scope of this cyanation reaction with respect to fuchsones as
an 1,6-acceptor (Table 3). Interestingly, fuchsones were also underwent 1,6- conjugate
addition reaction efficiently with tert-butyl isocyanide under the optimized reaction
conditions to produce α-triaryl nitriles in excellent yields. It should be noted that, in general
the synthesis of α-triaryl nitriles requires multistep processes and often difficult to access
a
these compounds due to steric constraints.8 Fuchsones possessing both electron-donating (-
Me, -OMe) (5b-5c), halo-substituted (-F, -Cl) (5d-5f) and electron withdrawing group (-CF3)
(5g) were well tolerated to afford the desired α-triaryl nitriles. Fuchsones bearing electron-
donating groups at the para positions showed higher reactivity than those bearing electron-
withdrawing groups.
Table 3. Substrate scope with different fuchsonesa
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O
OH
tBu
tBu
tBu
tBu
tBu-NC
2
( )
5
6
BF3.OEt2 (25 mol%)
CH2Cl2, rt
R'
R'
CN
R'
R'
7
4
5
8
9
OH
OH
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
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CN
CN
CN
CN
CN
Cl
Cl
Me
MeO
Cl
, 12 h, 87%
Me
, 12 h, 88%
OMe
, 12 h, 89%
5e
, 12 h, 86%
5b
5a
5c
, 12 h, 84%
5d
OH
OH
OH
OH
iPr
iPr
tBu
tBu
tBu
tBu
Me
Me
CN
CN
CN
CN
F
F3C
5g
, 12 h, 71%
5h
, 4 h, 90%
5i
, 4 h, 91%
5f
, 12 h, 85%
aPerformed with p-QMs 4 (0.1 mmol) Bu-NC 2 (0.15 mmol) and BF3.OEt2 (25 mol%) in CH2Cl2 (1 mL) at room
t
temperature.
Other fuchsones derived from 2,6-diisopropylphenol (4h) and 2,6-dimethylphenol (4i) were
also underwent smooth transformation to their corresponding α-triaryl nitriles 5h and 5i in
90 and 91% yields, respectively.
Based on the previous report,18 a plausible reaction mechanism for this
transformation is depicted in Scheme 1. The
BF3.Et2O and leading to the formation of highly electrophilic methylenic carbon.
Subsequent nucleophilic attack by tert-butyl isocyanide , forming zwitterionic
nitrilium ion intermediate . The nitrilium ion undergoes a loss of isobutylene,
p-QMs were activated by Lewis acid
2
A
A
results the formation of desired 1,6-conjugate addition product.
Scheme 1. Plausible reaction mechanism
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To further investigate the synthetic utility of this work, the transformation of 3a was
carried out (Scheme 2). The bulky tert-butyl group could easily be removed via
AlCl3 mediated retro-Friedel-Crafts reaction to afford the deprotected product 6a in
80% yield. The bromination of phenol 6a at the ortho-position using HBr in AcOH
resulted bromophenol 6b in 67 % yield. The bromide functionality can be easily
transformed to other functional groups. For an example, a Suzuki coupling was
performed on compound 6b to give the coupling product (6c) in 63% yield. Also, the
cyano product 3a could be easily transformed into amine
7 upon reduction using of
LiAlH4.
Scheme 2. Transformation of Compound 3a
In summary, we have developed a BF3.OEt2 catalyzed 1,6-conjugate addition of
tert-butyl isocyanide to para-quinone methides and fuchsones for the synthesis of
diaryl- and -triaryl nitriles. This method allows the facile access to the diverse range
of -diaryl- and
α-
α
α
α
-triaryl nitriles in good to excellent yields and with a broad substrate
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scope. This is the first example where tert-butyl isocyanide has been used as a cyanide
source for the 1,6-conjugate addition reaction. Importantly, these cyano-products
could be readily functionalized further to get a diverse set of products. The
development of an asymmetric version of this reaction is on-going in our laboratory.
EXPERIMENTAL SECTION
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1. General Information: Most of the reagents and starting materials used were
purchased from commercial sources and used as such. All the p-Quinone methides and
fuchsones were prepared by following a known literature procedures.20, 21 Melting points are
1
uncorrected and recorded using digital Buchi Melting Point Apparatus B-540. H, 13C and
19F NMR spectra were recorded on Bruker AV 200/400/500, AV 50/100/125 & AV 376 MHz
spectrometers respectively in CDCl3 using TMS as internal standard and the chemical shifts
1
are shown in δ scale. Multiplicities of H NMR signals are designated as s (singlet), d
(doublet), dd (doublet of doublet), t (triplet), quin (quintet), spt (septet) br.s. (broad signal), m
(multiplet) etc. HRMS (ESI) data were recorded on a Thermo Scientific Q-Exactive, Accela
1250 pump. Thin layer chromatography was performed on Merck silica gel 60 F254 TLC
plates using EtOAc/ hexane as an eluent. Column chromatography was carried out through
silica gel (100-200 mesh) using ethyl acetate/ hexane as an eluent.
2. Experimental Procedures:
A] General Procedure for BF3.OEt2 mediated cyanation of para-Quinone Methides
In a 5 mL reaction vial tert-butyl isocyanide 2 (0.22 mmol, 25 μL, 1.3 equiv) was added to
the mixture of p-QM 1 (0.17 mmol, 1 equiv) and DCM (1 mL). Then BF3.Et2O (0.042 mmol,
5 μL, 0.25 equiv) was added via syringe, and the reaction mixture was kept at room
temperature for ∼0.5 h. After the reaction was complete (detected by TLC) the solvent was
removed under reduced pressure and the residue was directly loaded on a silica gel column
and eluted using EtOAc/hexane mixture to obtain pure α-arylated nitrile (3).
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B] Procedure for Product transformations
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6
a) Procedure for synthesis of 6a:
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Dry MeNO2 (16 mL, 0.22 mmol) and AlCl3 (40 mg, 0.75 mmol) were added to flame-
dried glass flask under an atmosphere of nitrogen. The mixture was stirred for 30 min and
then 3a (50 mg, 0.15 mmol) in toluene (4 mL) were added. After stirring for 1h at room
temperature, the mixture was cooled to 0 °C and ice water was added to quench the AlCl3.
The mixture was extracted with EtOAc (3 × 15 mL), the combined organic layers were dried
(anhyd Na2SO4) and concentrated under reduced pressure followed by column
chromatography purification to afford the desired product 6a as a white solid in 80% yield.
b) Procedure for synthesis of 6b:
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To a stirred solution of 6a (50 mg, 0.24 mmol), HBr (45%, 0.8 mL) and AcOH (0.5 mL),
was added DMSO (0.25 mL) dropwise. The reaction progress was monitored by TLC. After
completion of the reaction, the system was extracted with ethyl acetate (3X10 mL). The
organic layers were combined, washed with brine (10 mL), dried with anhydrous Na2SO4 and
filtered. The filtrate was concentrated under reduced pressure. The residue was purified by
200– 300 mesh silica gel column chromatography (n-hexane/ethyl acetate=10:1) to give the
brominated product 6b as a yellow gummy solid in 67 % yield.
c) Procedure for synthesis of 6c:
To a solution of 6b (30 mg, 0.10 mmol) in THF/H2O (2 mL, 9:1) were added Pd(PPh3)4
(11 mg,0.010 mmol), phenylboronic acid (25 mg, 0.20 mmol), and Na2CO3 (22 mg, 0.15
mmol). The resulting mixture was stirred at 80°C for 4 h under N2. Water (10 mL) was added
and the system was extracted with CH2Cl2 (3X10 mL). The combined organic layers were
dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by 200–300 mesh silica gel column chromatography (n-
hexane/ethyl acetate=10:1) to give the coupling product 6c as a yellow gummy solid in 63 %
yield.
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d) Procedure for synthesis of 7:
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A round bottom flask was charged with LiAlH4 (12 mg, 0.311 mmol) and anhydrous
diethyl ether (4 mL). To the above suspension was added 3a (50 mg, 0.155 mmol) dissolved
in diethyl ether (1 mL) dropwise. The resulting suspension was stirred for 12 h at room
temperature. Reaction mixture was cooled at 0 °C and water was cautiously added until gas
evolution ceased, the aqueous layer was extracted with ether (10 ml x 2). The combined
organic layer was washed with brine and dried over Na2SO4. After evaporation of the organic
solvent, the crude amine was purified by using flash column chromatography (MeOH:DCM
3:97) as a viscous yellow liquid (7, 35 mg, 69 %).
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3. Characterization Data of Compounds:
4-(4-bromo-3-fluorobenzylidene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one(1s):
Yellow solid, 320 mg, 48% yield; mp= 118-120 °C; Rf= 0.85(petroleum ether/ethyl acetate =
99/01); 1H NMR (200 MHz, CDCl3) δ = 7.63 (t, J = 7.7 Hz, 1 H), 7.40 (d, J = 2.3 Hz, 1 H),
7.20 (dd, J = 1.8, 9.4 Hz, 1 H), 7.10 (dd, J = 1.4, 8.3 Hz, 1 H), 7.03 (s, 1 H), 6.97 (d, J = 2.3
Hz, 1 H), 1.32 (s, 9 H), 1.29 (s, 9 H), 13C{1H}NMR (100 MHz, CDCl3) δ =186.5, 160.3-
157.9 (d, J = 248.6 Hz), 152.8, 150.2, 148.5, 138.9-138.9 (d, J =2.9 Hz), 137.1 (d, J =7.3 Hz),
135.9, 134.6, 133.9-133.8 (d, J = 3.7 Hz), 133.1, 126.9 (d, J = 3.7 Hz), 126.8, 124.0, 117.8-
117.5 (d, J = 23.4 Hz), 110.0-109.8 (d, J = 20.5 Hz), 35.5, 35.1, 34.4, 30.3, 29.7, 29.5, 29.5;
19F NMR (376 MHz, CDCl3) δ = –106.33; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C21H25BrFO 391.1067; found 391.1071.
3-((3,5-di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)methyl)-4H-chromen-4-one (1t):
Yellow solid, 332 mg, 54% yield; mp= 190-192 °C; Rf= 0.85 (petroleum ether/ethyl acetate =
99/01); 1H NMR (200 MHz, CDCl3) δ = 8.37 - 8.20 (dd, J = 8.0 Hz, 1.2 Hz, 1 H), 8.07 (s, 1
H), 7.81 - 7.68 (m, 1 H), 7.57 - 7.42 (m, 2 H), 7.32 (d, J = 1.8 Hz, 1 H), 7.17 (s, 1 H), 7.08 (d,
13
J = 2.0 Hz, 1 H), 1.32 (s,9 H), 1.31 (s,9 H); C{1H} NMR (50 MHz,CDCl3) δ = 186.9,
176.3, 156.1, 155.2, 149.8, 148.0, 134.6, 134.3, 133.1, 131.9, 126.4, 126.3, 125.9, 123.8,
121.2, 118.3, 35.5, 35.0, 29.5, 29.4; HRMS (ESI-TOF) m/z: [M–H]– calcd for C24H25O3
361.1798; found 361.1797.
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2,6-di-tert-butyl-4-(diphenylmethylene)cyclohexa-2,5-dien-1-one (4a):
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Yellow solid, 635 mg, 63% yield; mp= 173-175 °C; Rf= 0.85 (petroleum ether/ethyl acetate
= 99/01); 1H NMR (200 MHz, CDCl3) δ = 7.39 - 7.30 (m, 6 H), 7.19 - 7.13 (m, 4 H), 7.11
(s, 2 H), 1.16 (s, 18 H); 13C{1H} NMR (50 MHz,CDCl3) δ = 186.2, 155.9, 147.5, 140.8,
131.9, 129.7, 129.1, 128.0, , 35.3, 29.5; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H31O
371.2369; found 371.2369.
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2,6-di-tert-butyl-4-(di-p-tolylmethylene)cyclohexa-2,5-dien-1-one (4b):
Yellow solid, 660 mg, 68% yield; mp= 177-179 °C; Rf= 0.85 (petroleum ether/ethyl acetate =
99/01); 1H NMR (200 MHz, CDCl3) δ = 7.24 - 7.08 (m, 10 H), 2.42 (s, 6 H), 1.25 (s, 18 H);
13C{1H} NMR (50 MHz,CDCl3) δ = 186.1, 156.8, 147.0, 139.4, 138.1, 132.3, 132.1, 129.2,
128.7, 35.2, 29.5, 21.4; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C29H35O 399.2682; found
399.2674.
4-(bis(4-methoxyphenyl)methylene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (4c) :
Yellow solid, 610 mg, 68% yield; mp= 174-176 °C; Rf= 0.60 (petroleum ether/ethyl acetate =
97/03); 1H NMR (200 MHz, CDCl3) δ = 7.23 - 7.11 (m, 6 H), 6.93 (d, J = 8.8 Hz, 4 H), 3.88
(s, 6 H), 1.26 (s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ = 186.0, 160.7, 156.5, 146.6,
134.0, 133.4, 132.4, 128.5, 113.4, 55.4, 35.2, 29.5; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C29H35O3 431.2581; found 431.2575.
4-(bis(4-chlorophenyl)methylene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (4d) :
Yellow solid, 550 mg, 62% yield; mp= 215-217 °C; Rf= 0.70 (petroleum ether/ethyl acetate =
98/02); 1H NMR (200 MHz, CDCl3) δ= 7.39 (d, J = 8.6 Hz, 4 H), 7.15 (d, J = 8.5 Hz, 4 H),
7.10 (s, 2 H), 1.23 (s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ = 186.0, 152.4, 148.1,
138.8, 135.6, 133.1, 131.2, 130.3, 128.5, 35.3, 29.5; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C27H29Cl2O 439.1590; found 439.1579.
2,6-di-tert-butyl-4-((4-chlorophenyl)(phenyl)methylene)cyclohexa-2,5-dien-1-one (4e) :
Yellow solid, 580 mg, 59% yield; mp= 189-191 °C; Rf= 0.75 (petroleum ether/ethyl acetate
= 99/01); 1H NMR (400 MHz, CDCl3) δ = 7.47 - 7.33 (m, 5 H), 7.25 - 7.12 (m, 6 H), 1.25
13
(s, 9 H), 1.23 (s, 9 H); C{1H} NMR (100 MHz, CDCl3) δ = 186.1, 154.1, 147.9, 147.7,
140.4, , 133.1, 131.8, 131.7, 131.3, 130.0, 129.3, 128.3, 128.1, 35.3, 35.3, 29.5, 29.4; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C27H30ClO 405.1980; found 405.1973.
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2,6-di-tert-butyl-4-((4-fluorophenyl)(phenyl)methylene)cyclohexa-2,5-dien-1-one (4f) :
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Yellow solid, 560 mg, 57% yield; mp= 186-188 °C; Rf= 0.75 (petroleum ether/ethyl acetate =
99/01); 1H NMR (400 MHz, CDCl3) δ = 7.51 - 7.36 (m, 3 H), 7.27 - 7.19 (m, 4 H), 7.17 -
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7.05 (m, 4 H), 1.24 (s, 9 H), 1.23 (s, 9 H); C{1H} NMR (100 MHz, CDCl3) δ = 186.1,
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164.4-161.9 (d, J = 251.23 Hz), 154.5, 147.7- 147.6 (d, J = 13.10 Hz), 140.6, 136.8, 133.8-
133.7 (d, J = 7.71 Hz), 131.9, 131.8, 131.5, 129.8, 129.3, 128.1, 125.9, 115.3-115.1(d, J =
19
21.58 Hz), 35.3, 30.3, 29.5, 29.5; F NMR (376 MHz, CDCl3) δ = –111.28; HRMS (ESI-
TOF) m/z: [M+H]+ calcd for C27H30FO 389.2275; found 389.2269.
2,6-di-tert-butyl-4-(phenyl(4-(trifluoromethyl)phenyl)methylene)cyclohexa-2,5-dien-1-
one (4g) :
Yellow solid, 490 mg, 55% yield; mp= 191-193 °C; Rf= 0.75 (petroleum ether/ethyl acetate =
1
99/01); H NMR (200 MHz, CDCl3) δ = 7.67 (d, J = 8.1 Hz, 2 H), 7.47 - 7.33 (m, 5 H),
7.21 (dd, J = 2.5, 6.3 Hz, 3 H), 7.08 (d, J = 2.4 Hz, 1 H), 1.23 (s, 18 H); 13C{1H} NMR (50
MHz, CDCl3) δ = 186.1, 153.3, 148.2 (d, J= 5.8 Hz), 144.4, 140.2, 131.8 (d, J= 12.4 Hz),
19
131.2 (d, J= 27.8 Hz), 130.6, 129.4, 128.2, 124.9 (d, J= 3.2 Hz), 35.4, 29.5; F NMR (376
MHz, CDCl3) δ = –62.64; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C28H30F3O 439.2243;
found 439.2231.
4-(diphenylmethylene)-2,6-diisopropylcyclohexa-2,5-dien-1-one (4h) :
Yellow solid, 560 mg, 61% yield; mp= 147-148 °C; Rf= 0.75 (petroleum ether/ethyl acetate =
99/01); 1H NMR (200 MHz, CDCl3) δ = 7.56 - 7.35 (m, 6 H), 7.29 - 7.19 (m, 4 H), 7.12 (s,
2 H), 3.18 (spt, J = 6.9 Hz, 2 H), 1.06 (d, J = 6.8 Hz, 12 H) 13C{1H} NMR (50 MHz,
CDCl3) δ = 185.0, 156.5, 145.5, 140.7, 132.1, 131.7, 130.0, 129.3, 128.0, 26.8, 22.0;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C25H27O 343.2056; found 343.2057.
4-(diphenylmethylene)-2,6-dimethylcyclohexa-2,5-dien-1-one (4i) :
Yellow solid, 480 mg, 57% yield; mp= 180-183 °C; Rf= 0.75 (petroleum ether/ethyl acetate =
99/01); 1H NMR (200 MHz, CDCl3) δ = 7.46 - 7.39 (m, 5 H), 7.31 - 7.17 (m, 5 H), 7.16 (s,
2 H), 2.02 (s, 6 H) ; 13C{1H} NMR (50 MHz, CDCl3) δ = 187.1, 156.5, 140.6, 135.7, 135.4,
131.9, 129.8, 129.3, 128.0, 16.7 ; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C21H19O
287.1430; found 287.1433.
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2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylacetonitrile (3a) :
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White solid, 49 mg, 90 % yield; mp= 108‒110 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
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95/05); H NMR (400 MHz, CDCl3) δ = 7.41 - 7.30 (m, 5 H), 7.10 (s, 2 H), 5.26 (s, 1 H),
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5.07 (s, 1 H), 1.41 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ = 153.6, 136.6, 136.4,
129.0, 128.0, 127.6, 126.5, 124.5, 120.3, 42.5, 34.4, 30.1; HRMS (ESI-TOF) m/z: [M–H]–
calcd for C22H26NO 320.2009; found 320.2024.
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2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(p-tolyl)acetonitrile (3b) :
Yellow solid, 46 mg, 85% yield; mp= 107-109 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (400 MHz, CDCl3) δ = 7.25 (d, J= 8.2, 2H), 7.18 (d, J= 8.2, 2H), 7.10 (s, 2
13
H), 5.24 (s, 1 H), 5.03 (s, 1 H), 2.35 (s, 3 H), 1.41 (s, 18 H) ; C{1H} NMR (100 MHz,
CDCl3) δ = 153.6, 137.7, 136.5, 133.5, 129.7, 127.5, 126.7, 124.4, 120.5, 42.2, 34.4, 30.1,
21.0; HRMS (ESI-TOF) m/z: [M–H]– calcd for C23H28NO 334.2165; found 334.2178.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-isopropylphenyl)acetonitrile (3c) :
Yellow solid, 42 mg, 78% yield; mp= 70-72 °C; Rf= 0.40 (petroleum ether/ethyl acetate =
95/05); 1H NMR (400 MHz, CDCl3) δ = 7.28 (d, J= 8.4, 2H), 7.22 (d, J= 8.4, 2H), 7.12 (s, 2
H), 5.25 (s, 1 H), 5.03 (s, 1 H), 2.91 (spt, J = 6.9 Hz, 1 H), 1.42 (s, 18 H), 1.24 (d, J = 6.9 Hz,
6 H); 13C{1H} NMR (100 MHz, CDCl3) δ = 153.6, 148.7, 136.6, 133.8, 127.5, 127.1, 126.7,
124.5, 120.6, 42.2, 34.4, 33.8, 30.3, 30.2, 23.9; HRMS (ESI-TOF) m/z: [M–H]– calcd for
C25H32NO 362.2478; found 362.2494.
2-(4-(tert-butyl)phenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3d) :
Yellow gummy solid, 39 mg, 72 % yield; Rf= 0.40 (petroleum ether/ethyl acetate = 95/05);
1H NMR (200 MHz, CDCl3) δ = 7.39 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.12 (s,
13
2 H), 5.25 (s, 1 H), 5.03 (s, 1 H), 1.42 (s, 18 H), 1.32 (s, 9 H); C{1H} NMR (50 MHz,
CDCl3) δ = 153.6, 150.9, 136.5, 133.5, 127.2, 126.6, 125.9, 124.5, 120.5, 42.1, 34.5, 34.4,
31.2, 30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd for C26H34NO 376.2635; found 376.2650.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-methoxyphenyl)acetonitrile (3e) :
Pale yellow solid, 48 mg, 89% yield; mp= 96-97 °C; Rf= 0.30 (petroleum ether/ethyl acetate
= 95/05); 1H NMR (400 MHz, CDCl3) δ = 7.28 (d, J = 8.2 Hz, 2 H), 7.10 (s, 2 H), 6.91 (d, J
= 8.2 Hz, 2 H), 5.26 (s, 1 H), 5.04 (s, 1 H), 3.83 (s, 3 H), 1.43 (s, 18 H); 13C{1H} NMR (100
MHz, CDCl3) δ = 159.3, 153.6, 136.6, 128.8, 128.5, 126.8, 124.4, 120.6, 114.4, 55.3, 41.8,
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34.4, 30.2; HRMS (ESI-TOF) m/z: [M–H]– calcd for C23H28NO2 350.2115; found
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350.2130.
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2-(4-(benzyloxy)phenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3f) :
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White solid, 52 mg, 97% yield; mp= 86-88°C; Rf= 0.25 (petroleum ether/ethyl acetate =
95/05); 1H NMR (500 MHz, CDCl3) δ = 7.43 (d, J = 7.2 Hz ,2 H), 7.39 (t, J = 7.2 Hz, 2 H),
7.33 (t, J = 7.2 Hz ,1 H), 7.28 (d, J = 8.8 Hz, 2 H), 7.10 (s, 2 H), 6.98 (d, J = 8.8 Hz, 2 H),
5.25 (s, 1 H), 5.07 (s, 2 H), 5.02 (s, 1 H), 1.42 (s, 18 H) ; 13C{1H} NMR (50 MHz, CDCl3) δ
= 158.4, 153.5, 136.7, 136.5, 128.8, 128.6, 128.0, 127.4, 126.7, 124.4, 120.5, 115.3, 70.0,
41.7, 34.4, 30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd for C29H32NO2 426.2428; found
426.2444.
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2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-(dimethylamino)phenyl)acetonitrile (3g) :
Light pink solid, 52 mg, 96% yield; mp= 138-140 °C; Rf= 0.50 (petroleum ether/ethyl acetate
= 95/05); 1H NMR (400 MHz, CDCl3) δ = 7.20 (d, J = 7.9 Hz, 2 H), 7.12 (s, 2 H), 6.72 (d, J
= 8.5 Hz, 2 H), 5.23 (s, 1 H), 4.99 (s, 1 H), 2.96 (s, 6 H), 1.42 (s, 18 H); 13C{1H} NMR (100
MHz, CDCl3) δ = 153.4, 149.9, 136.4, 128.3, 127.2, 124.3, 120.9, 112.8, 41.7, 40.6, 34.4,
30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd for C24H31N2O 363.2449; found 363.2431.
2-(4-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3h) :
Yellow gummy solid, 42 mg, 78% yield; Rf= 0.50 (petroleum ether/ethyl acetate = 95/05); 1H
NMR (200 MHz, CDCl3) δ = 7.36 (d, J = 8.8 Hz ,2 H), 7.28 (d, J = 8.8 Hz ,2 H), 7.07 (s, 2
H), 5.28 (s, 1 H), 5.03 (s, 1 H), 1.41 (s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ = 153.8,
136.8, 135.0, 134.0, 129.3, 129.0, 126.0, 124.4, 119.9, 42.0, 34.5, 30.1; HRMS (ESI-TOF)
m/z: [M–H]– calcd for C22H25ClNO 354.1619; found 354.1633.
2-(4-bromophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3i) :
Yellow solid, 43 mg, 81% yield; mp= 150-152 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (200 MHz, CDCl3) δ = 7.51 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2 H),
7.08 (s, 2 H), 5.29 (s, 1 H), 5.02 (s, 1 H), 1.42 (s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ
= 153.8, 136.8, 135.5, 132.2, 129.3, 125.9, 124.4, 122.1, 119.8, 42.0, 34.4, 30.1; HRMS
(ESI-TOF) m/z: [M–H]– calcd for C22H25BrNO 398.1114; found 398.1130.
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2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-(trifluoromethyl)phenyl)acetonitrile (3j) :
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White solid, 37 mg, 70% yield; mp= 133-135 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H),
7.09 (s, 2 H), 5.30 (s, 1 H), 5.11 (s, 1 H), 1.41 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ
= 153.9, 140.4, 136.9, 128.0, 126.9 (q, J= 3.8 Hz), 125.5, 124.4, 119.5, 42.4, 34.4, 30.1; 19F
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NMR (376 MHz, CDCl3) δ = –62.66;
HRMS (ESI-TOF) m/z: [M–H]– calcd for
C23H25F3NO 388.1883; found 388.1902.
4-(cyano(3,5-di-tert-butyl-4-hydroxyphenyl)methyl)benzonitrile (3k) :
White solid, 32 mg, 59% yield; mp= 144-145 °C; Rf= 0.40 (petroleum ether/ethyl acetate =
95/05); 1H NMR (200 MHz, CDCl3) δ = 7.69 (d, J = 8.3 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H),
7.05 (s, 2 H), 5.32 (s, 1 H), 5.10 (s, 1 H), 1.40 (s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ
= 154.1, 141.6, 137.1, 132.9, 128.5, 125.1, 124.5, 119.2, 112.2, 42.6, 34.5, 30.1; HRMS
(ESI-TOF) m/z: [M–H]– calcd for C23H25N2O 345.1961; found 345.1976.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-nitrophenyl)acetonitrile (3l) :
Off white solid, 34 mg, 64% yield; mp= 113-114 °C; Rf= 0.30 (petroleum ether/ethyl acetate
= 95/05); 1H NMR (400 MHz, CDCl3) δ = 8.27 - 8.22 (d, J = 9.2 Hz, 2 H), 7.58 - 7.53 (d, J =
8.7 Hz, 2 H), 7.07 (s, 2 H), 5.33 (s, 1 H), 5.15 (s, 1 H), 1.41 (s, 18 H); C{1H} NMR (100
13
MHz, CDCl3) δ = 154.1, 147.6, 143.4, 137.1, 128.6, 125.0, 124.4, 124.3, 119.1, 42.3, 34.4,
30.0; HRMS (ESI-TOF) m/z: [M–H]– calcd for C22H25N2O3 365.1860; found 365.1871.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(2-methoxyphenyl)acetonitrile (3m) :
Off white solid, 43 mg, 79% yield; mp= 107-108 °C; Rf= 0.40 (petroleum ether/ethyl acetate
= 95/05); 1H NMR (400 MHz, CDCl3) δ = 7.32 (d, J = 7.9 Hz, 1 H), 7.28 (m, 1 H), 7.17 (s, 2
H), 6.94 (t, J = 7.6 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 5.45 (s, 1 H), 5.29 (s, 1 H), 3.87 (s, 3
H), 1.40 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ = 156.0, 153.4, 136.2, 129.3, 128.6,
126.1, 125.3, 124.5, 121.0, 120.6, 110.8, 55.5, 36.1, 34.4, 30.2; HRMS (ESI-TOF) m/z: [M–
H]– calcd for C23H28NO2 350.2115; found 350.2129.
2-(2-bromophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3n) :
White solid, 40 mg, 75% yield; mp= 109-110 °C; Rf= 0.65 (petroleum ether/ethyl acetate =
95/05); 1H NMR (200 MHz, CDCl3) δ = 7.60 (d, J = 8.1 Hz, 1 H), 7.53 (dd, J = 1.3, 7.8 Hz,
1 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.23 (d, J = 1.5 Hz, 1 H), 7.18 (s, 2 H), 5.56 (s, 1 H), 5.26 (s, 1
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H), 1.41 (s, 18 H); C{1H} NMR (50 MHz, CDCl3) δ = 153.7, 136.5, 136.2, 133.3, 129.8,
129.7, 128.3, 125.1, 124.5, 123.5, 119.8 , 41.8, 34.4, 30.1; HRMS (ESI-TOF) m/z: [M–H]–
calcd for C22H25BrNO 398.1114; found 398.1133.
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Yellow gummy solid, 38 mg,70% yield; Rf= 0.50 (petroleum ether/ethyl acetate = 95/05); H
NMR (200 MHz, CDCl3) δ = 7.41 - 7.32 (m, 2 H), 7.32 - 7.20 (m, 2 H), 7.09 (s, 2 H), 5.30
(s, 1 H), 5.03 (s, 1 H), 1.42 (s, 18 H); C{1H} NMR (50 MHz, CDCl3) δ = 153.9, 138.3,
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136.8, 134.9, 130.3, 128.3, 127.8, 125.8, 125.7, 124.4, 119.7, 42.2, 34.4, 30.1; HRMS (ESI-
TOF) m/z: [M–H]– calcd for C22H25ClNO 354.1619; found 354.1633.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(3-fluorophenyl)acetonitrile (3p) :
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Yellow gummy solid, 36 mg, 66% yield; Rf= 0.50(petroleum ether/ethyl acetate = 95/05); H
NMR (500 MHz, CDCl3) δ = 7.38 (dt, J = 6.1, 8.0 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.12
(s, 2 H), 7.10 - 7.01 (m, 2 H), 5.31 (s, 1 H), 5.08 (s, 1 H), 1.44 (s, 18 H); 13C{1H} NMR (125
MHz, CDCl3) δ = 162.9 (d, J = 247.0 Hz), 153.9, 138.8 (d, J = 6.8 Hz), 136.8, 130.6 (d, J =
7.6 Hz), 125.8, 124.5, 123.3 (d, J = 2.8 Hz), 119.8, 115.0 (d, J = 20.9 Hz), 114.8 (d, J = 22.8
Hz), 42.2, 34.4, 30.1; 19F NMR (376 MHz, CDCl3) δ = –111.57; HRMS (ESI-TOF) m/z:
[M–H]– calcd for C22H25FNO 338.1915; found 338.1928.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(2,4-dichlorophenyl)acetonitrile (3q) :
White solid, 36 mg, 63% yield; mp= 120-122 °C; Rf= 0.40 (petroleum ether/ethyl acetate =
95/05); 1H NMR (200 MHz, CDCl3) δ = 7.47 - 7.43 (d, J = 2.2 Hz, 1 H), 7.42 (d, J = 6.1 Hz,
1 H), 7.34 - 7.27 (dd, J = 8.3 Hz, 2.2 Hz, 1 H), 7.13 (s, 2 H), 5.48 (s, 1 H), 5.29 (s, 1 H), 1.41
(s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ = 153.9, 136.7, 134.8, 133.7, 133.2, 130.3,
129.8, 128.0, 124.5, 124.4, 119.3, 38.9, 34.4, 30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd
for C22H24Cl2NO 388.1229; found 388.1245.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)acetonitril (3r) :
White solid, 52 mg, 98% yield; mp= 130-131 °C; Rf= 0.30 (petroleum ether/ethyl acetate =
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90/10); H NMR (400 MHz, CDCl3) δ = 7.10 (s, 2 H), 6.92 - 6.79 (m, 3 H), 5.26 (s, 1 H),
5.02 (s, 1 H), 3.86 (s, 3 H), 3.88 (s, 3 H), 1.41 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ
= 153.6, 149.3, 148.7, , 136.6, 128.7, 126.5, 124.3, 120.5, 120.1, 111.3, 110.7, 55.9, 42.0,
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34.4, 30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd for C24H30NO3 380.2220; found
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380.2236.
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2-(4-bromo-3-fluorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3s) :
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Off white solid, 28 mg, 52% yield; mp= 78-80 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (400 MHz, CDCl3) δ = 7.56 (t, J = 7.8 Hz, 1 H), 7.14 - 7.02 (m, 4 H), 5.31
(s, 1 H), 5.01 (s, 1 H), 1.41 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ = 160.4-158.0 (d,
J= 248.9 Hz), 154.0, 138.2-138.1 (d, J= 6.9 Hz), 137.0, 134.1, 125.3, 124.4, 119.3, 116.1-
115.8 (d, J= 23.8 Hz), 108.9-108.7 (d, J= 20.8 Hz), 41.9, 34.5, 30.1; 19F NMR (376 MHz,
CDCl3) δ = –105.37; HRMS (ESI-TOF) m/z: [M–H]– calcd for C22H24BrFNO 416.1040;
found 416.1020.
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2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-oxo-4H-chromen-3-yl)acetonitrile (3t) :
Off white solid, 26 mg, 48% yield; mp= 135-137 °C; Rf= 0.30 (petroleum ether/ethyl acetate
= 95/05); 1H NMR (200 MHz, CDCl3) δ = 8.24 (dd, J = 1.4, 8.0 Hz, 1 H), 7.98 (s, 1 H), 7.76
- 7.63 (m, 1 H), 7.51 - 7.38 (m, 2 H), 7.26 (s, 2 H), 5.42 (s, 1 H), 5.30 (s, 1 H), 1.43 (s, 18 H);
13C{1H} NMR (50 MHz, CDCl3) δ = 175.1, 156.3, 154.0, 153.9, 136.8, 134.2, 126.1, 125.6,
124.5, 124.1, 123.6, 122.0, 119.2, 118.2, 34.4, 32.8, 30.1; HRMS (ESI-TOF) m/z: [M–H]–
calcd for C25H26NO3 388.1907; found 388.1919.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(thiophen-2-yl)acetonitrile (3u) :
Orange gummy solid, 42 mg, 77% yield; Rf= 0.40 (petroleum ether/ethyl acetate = 95/05); 1H
NMR (200 MHz, CDCl3) δ = 7.30 - 7.24 (m, 1 H), 7.18 (s, 2 H), 7.12 - 7.03 (m, 1 H), 7.03 -
6.93 (m, 1 H), 5.30 (s, 1 H), 5.28 (s, 1 H), 1.43 (s, 18 H) ; 13C{1H} NMR (50 MHz, CDCl3) δ
= 154.0, 139.4, 136.7, 127.0, 126.4, 126.1, 124.3, 119.4, 37.9, 34.4, 30.1; HRMS (ESI-
TOF) m/z: [M–H]– calcd for C20H24NOS 326.1573; found 326.1587.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(furan-2-yl)acetonitrile (3v) :
Orange gummy solid, 36 mg, 65% yield; Rf= 0.30 (petroleum ether/ethyl acetate = 95/05); 1H
NMR (400 MHz, CDCl3) δ = 7.41 (s, 1 H), 7.15 (s, 2 H), 6.35 (dd, J = 2.0, 3.1 Hz, 1 H),
6.33 - 6.19 (d, J = 3.2, 1 H), 5.30 (s, 1 H), 5.11 (s, 1 H), 1.43 (s, 18 H); 13C{1H} NMR (100
MHz, CDCl3) δ = 154.0, 148.5, 143.2, 136.7, 124.4, 123.6, 118.1, 110.7, 108.3, 36.7, 34.4,
30.1;; HRMS (ESI-TOF) m/z: [M–H]– calcd for C20H24NO2 310.1802; found 310.1815.
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2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(naphthalen-1-yl)acetonitrile (3x) :
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Off white solid, 43 mg, 80% yield; mp= 144-145 °C; Rf= 0.40 (petroleum ether/ethyl acetate
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= 95/05); H NMR (400 MHz, CDCl3) δ = 7.99 (d, J = 7.9 Hz, 1 H), 7.94 - 7.85 (m, 2 H),
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(s, 18 H); C{1H} NMR (100 MHz, CDCl3) δ = 153.6, 136.5, 134.0, 131.6, 130.5, 129.2,
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129.1, 126.8, 126.7, 126.1, 125.5, 125.4, 124.6, 123.0, 120.5, 39.5, 34.4, 30.1; HRMS (ESI-
TOF) m/z: [M–H]– calcd for C26H28NO 370.2165; found 370.2184.
2-(anthracen-9-yl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3y) :
Yellow solid, 42 mg, 79% yield; mp= 193-195 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (400 MHz, CDCl3) δ = 8.56 (s, 1 H), 8.21 (d, J = 8.4 Hz, 2 H), 8.07 (dd, J
= 7.6 Hz 2 H), 7.61 - 7.43 (m, 4 H), 7.13 (s, 2 H), 6.67 (s, 1 H), 5.20 (s, 1 H), 1.29 (s, 18 H);
13C{1H} NMR (100 MHz, CDCl3) δ = 153.3, 136.5, 131.6, 129.9, 129.5, 129.4, 126.8, 125.6,
125.5, 125.1, 123.9, 123.7, 120.5, 35.0, 34.4, 30.0; HRMS (ESI-TOF) m/z: [M+Na]+ calcd
for C30H31NONa 444.2298, found 444.2299.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(9H-fluoren-3-yl)acetonitrile (3z) :
White solid, 45 mg, 84% yield; mp= 187-189 °C; Rf= 0.30 (petroleum ether/ethyl acetate =
95/05); 1H NMR (200 MHz, CDCl3) δ = 7.78 (d, J = 8.2 Hz, 2 H), 7.60 - 7.51 (m, 2 H), 7.45
- 7.27 (m, 3 H), 7.15 (s, 2 H), 5.27 (s, 1 H), 5.15 (s, 1 H), 3.91 (s, 2 H), 1.42 (s, 18 H);
13C{1H} NMR (50 MHz, CDCl3) δ = 153.6, 144.1, 143.4, 141.6, 140.9, 136.6, 134.8, 127.0,
126.8, 126.8, 126.4, 125.1, 124.4, 124.3, 120.5, 120.2, 120.0, 42.6, 36.9, 34.4, 30.1; HRMS
(ESI-TOF) m/z: [M–H]– calcd for C29H30NO 408.2322; found 408.2334.
2-([1,1'-biphenyl]-4-yl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (3aa) :
White solid, 44 mg, 82% yield; mp= 133-135 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (400 MHz, CDCl3) δ = 7.68 - 7.54 (m, 4 H), 7.53 - 7.31 (m, 5 H), 7.16 (s, 2
H), 5.29 (s, 1 H), 5.12 (s, 1 H), 1.44 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3) δ = 153.7,
140.9, 140.2, 136.7, 135.4, 128.8, 128.0, 127.7, 127.6, 127.0, 126.4, 124.5, 120.3, 42.2, 34.4,
30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd for C28H30NO 396.2322; found 396.2334.2-
(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(2-(phenylethynyl)phenyl)acetonitrile (3ab) :
Off white solid, 43 mg, 80% yield; mp= 64-66 °C; Rf= 0.40 (petroleum ether/ethyl acetate =
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95/05); H NMR (400 MHz, CDCl3) δ = 7.61 - 7.54 (m, 2 H), 7.52 (dd, J = 2.7, 6.5 Hz, 2
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H), 7.42 - 7.29 (m, 5 H), 7.24 (s, 2 H), 5.73 (s, 1 H), 5.22 (s, 1 H), 1.36 (s, 18 H);
13C{1H}NMR (100 MHz, CDCl3) δ = 153.6, 138.4, 136.5, 132.6, 131.6, 129.2, 128.8, 128.4,
128.0, 127.8, 126.1, 124.3, 122.5, 122.2, 120.2, 95.2, 86.8, 40.5, 34.4, 30.1; HRMS (ESI-
TOF) m/z: [M–H]– C30H30NO 420.2322; found 420.2336.
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2-(4-hydroxy-3,5-diisopropylphenyl)-2-phenylacetonitrile (3ac) :
White solid, 43 mg, 78% yield; mp= 99-100 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
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90/10); H NMR (500 MHz, CDCl3) δ = 7.39 - 7.28 (m, 5 H), 6.99 (s, 2 H), 5.08 (s, 1 H),
4.97 (br. s., 1 H), 3.13 (spt, J = 6.8 Hz, 2 H), 1.23 (d, J = 6.9 Hz, 12 H); 13C{1H} NMR (125
MHz, CDCl3) δ = 149.9, 136.4, 134.6, 129.8, 129.0, 127.9, 127.5, 123.0, 120.2, 42.3, 27.3,
22.5; HRMS (ESI-TOF) m/z: [M–H]– calcd for C20H22NO 292.1696; found 292.1710.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-diphenylacetonitrile (5a):
Off white solid, 43 mg, 80% yield; mp = 137-138 °C; Rf= 0.60 (petroleum ether/ethyl acetate
= 98/02); 1H NMR (400 MHz, CDCl3) δ = 7.35 (m, 6 H), 7.23 (d, J=6.10 Hz, 4 H), 6.97 (s, 2
13
H), 5.29 (s, 1 H), 1.35 (s, 18 H); C{1H} NMR (100 MHz, CDCl3) δ = 153.7, 141.3, 136.1,
130.7, 129.1, 128.8, 128.2, 126.1, 124.2, 57.6, 34.8, 30.4; HRMS (ESI-TOF) m/z: [M–H]–
calcd for C28H30NO 396.2322; found 396.2338.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-di-p-tolylacetonitrile (5b):
Off white solid, 45 mg, 84% yield; mp= 141-143 °C; Rf= 0.70 (petroleum ether/ethyl acetate
= 98/02); 1H NMR (400 MHz, CDCl3) δ = 7.13 (d, J=7.93 Hz, 4 H), 7.09 (d, J=7.93 Hz, 4
H), 6.97 (s, 2 H), 5.25 (s, 1 H), 2.35 (s, 6 H), 1.34 (s, 18 H); 13C{1H} NMR (100
MHz,CDCl3) δ = 153.6, 138.6, 137.8, 136.0, 131.0, 129.4, 128.9, 126.0, 124.4, 57.0, 34.8,
30.5, 21.3; HRMS (ESI-TOF) m/z: [M–H]– calcd for C30H34NO 424.2635; found 424.2653.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,2-bis(4-methoxyphenyl)acetonitrile (5c):
Yellow solid, 43 mg, 81% yield; mp= 135-136 °C; Rf= 0.40 (petroleum ether/ethyl acetate =
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95/05); H NMR (400 MHz, CDCl3) δ = 7.12 (d, J=8.54 Hz, 4 H) 6.98 (s, 2 H) 6.86 (d,
J=8.55 Hz, 4 H) 5.27 (s, 1 H) 3.81 (s, 6 H) 1.35 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3)
δ = 159.0, 153.3, 135.7, 133.4, 131.0, 129.8, 125.5, 124.1, 113.7, 55.9, 55.3, 34.4, 30.1;
HRMS (ESI-TOF) m/z: [M–H]– calcd for C30H34NO3 456.2533; found 456.2552.
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2,2-bis(4-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)acetonitrile (5d):
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Off white solid, 44 mg, 83% yield; mp= 166-168 °C; Rf= 0.50 (petroleum ether/ethyl acetate
= 95/05); 1H NMR (200 MHz, CDCl3) δ = 7.34 (d, J=8.84 Hz, 4 H) 7.14 (d, J=8.84 Hz, 4 H)
6.93 (s, 2 H) 5.33 (s, 1 H) 1.34 (s, 18 H); 13C{1H} NMR (50 MHz, CDCl3) δ = 153.7, 139.2,
136.2, 134.2, 130.0, 129.5, 128.8, 125.4, 123.0, 56.3, 34.5, 30.1; HRMS (ESI-TOF) m/z:
[M–H]– calcd for C28H28Cl2NO 464.1542; found 464.1562.
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2-(4-chlorophenyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenylacetonitrile (5e):
Off white solid, 44 mg, 82% yield; mp= 117-118 °C; Rf= 0.50 (petroleum ether/ethyl acetate
= 98/02); 1H NMR (400 MHz, CDCl3) δ = 7.39 - 7.36 (m, 1 H), 7.36 - 7.33 (m, 3 H), 7.33 -
7.31 (m, 1 H), 7.22 (d, J = 1.8 Hz, 1 H), 7.20 (d, J = 1.8 Hz, 1 H), 7.19 - 7.17 (m, 1 H), 7.17 -
7.14 (m, 1 H), 6.95 (s, 2 H), 5.31 (s, 1 H), 1.35 (s, 18 H); 13C{1H} NMR (100 MHz, CDCl3)
δ = 153.6, 140.4, 139.7, 136.0, 134.0, 130.1, 129.9, 128.6, 128.6, 128.1, 125.6, 123.4, 56.8,
34.4, 30.1; HRMS (ESI-TOF) m/z: [M–H]– calcd for C28H29ClNO 430.1932; found
430.1949.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-(4-fluorophenyl)-2-phenylacetonitrile (5f):
Off white solid, 43 mg, 80% yield; mp= 134-136 °C; Rf= 0.50 (petroleum ether/ethyl acetate
= 98/02); 1H NMR (500 MHz, CDCl3) δ = 7.37 (m, 3 H), 7.22 (m, 4 H), 7.06 (m, 2 H), 6.97
(s, 2 H), 5.33 (s, 1 H), 1.38 (s, 18 H); 13C{1H} NMR (125 MHz, CDCl3) δ = 163.2-161.2 (d,
J = 247.96 Hz), 153.5, 140.8, 136.9, 136.0, 130.6-130.5 (d, J = 7.63 Hz), 130.3, 128.6 (d, J
=6.6 Hz), 128.0, 125.6, 123.7, 115.5-115.3 (d, J = 21.93 Hz), 56.7, 34.5, 30.1; 19F NMR (376
MHz, CDCl3) δ = –114.16; HRMS (ESI-TOF) m/z: [M–H]– calcd for C28H29FNO
414.2228; found 414.2248.
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-phenyl-2-(4-(trifluoromethyl)phenyl)acetonitrile
(5g) :
Off white solid, 40 mg, 75% yield; mp= 128-129 °C; Rf= 0.40 (petroleum ether/ethyl acetate
= 98/02); 1H NMR (200 MHz, CDCl3) δ = 7.62 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 7.1 Hz, 5
H), 7.26 - 7.12 (m, 2 H), 6.94 (s, 2 H), 5.33 (s, 1 H), 1.34 (s, 18 H); 13C{1H} NMR (50 MHz,
CDCl3) δ = 153.7, 145.1, 140.1, 136.2, 129.6, 129.2, 128.7, 128.7, 128.3, 125.6, 125.5,
125.4, 123.2, 34.5, 30.1; 19F NMR (376 MHz, CDCl3) δ = –62.65; HRMS (ESI-TOF) m/z:
[M–H]– calcd for C29H29F3NO 464.2196; found 464.2210.
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2-(4-hydroxy-3,5-diisopropylphenyl)-2,2-diphenylacetonitrile (5h) :
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White solid, 48 mg, 90% yield; mp= 149-151 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (500 MHz, CDCl3) δ = 7.44 - 7.30 (m, 6 H), 7.29 - 7.10 (m, 4 H), 6.85 (s, 2
H), 4.95 (s, 1 H), 3.12 (spt, J = 6.8 Hz, 2 H), 1.16 (d, J = 6.8 Hz, 12 H); 13C{1H} NMR (125
MHz, CDCl3) δ = 149.7, 140.9, 133.8, 131.7, 128.7, 128.5, 127.9, 124.2, 123.8, 57.1, 27.3,
22.5; HRMS (ESI-TOF) m/z: [M–H]– calcd for C26H26NO 368.2009; found 368.2022.
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2-(4-hydroxy-3,5-dimethylphenyl)-2,2-diphenylacetonitrile (5i) :
White solid, 50 mg, 91% yield; mp= 177-178 °C; Rf= 0.50 (petroleum ether/ethyl acetate =
95/05); 1H NMR (500 MHz, CDCl3) δ = 7.42 - 7.34 (m, 6 H), 7.31 - 7.20 (m, 4 H), 6.83 (s, 2
H), 4.90 (s, 1 H), 2.22 (s, 6 H) ; 13C{1H} NMR (125 MHz, CDCl3) δ = 152.0, 140.6, 131.5,
129.0, 128.7, 128.5, 128.0, 123.8, 123.2, 56.8, 16.1; HRMS (ESI-TOF) m/z: [M–H]– calcd
for C22H18NO 312.1383; found 312.1395.
2-(4-hydroxyphenyl)-2-phenylacetonitrile (6a) :
White solid, 26mg, 80% yield; mp= 106-108 °C; Rf= 0.65 (petroleum ether/ethyl acetate =
80/20); 1H NMR (400 MHz, CDCl3) δ = 7.39 - 7.30 (m, 5 H), 7.17 (d, J = 8.4 Hz, 2 H), 6.83
13
(d, J = 9.2 Hz, 2 H), 5.91 (br. s., 1 H), 5.09 (s, 1 H) ; C{1H} NMR (100 MHz, CDCl3) δ =
155.7, 135.9, 129.1, 129.0, 128.2, 127.6, 127.5, 120.0, 116.0, 41.7 ; HRMS (ESI-TOF) m/z:
[M–H]– calcd for C14H10NO 208.0757; found 208.0763.
2-(3-bromo-4-hydroxyphenyl)-2-phenylacetonitrile (6b) :
Yellow gummy solid, 46 mg, 67% yield; Rf= 0.50 (petroleum ether/ethyl acetate = 80/20); 1H
NMR (400 MHz, CDCl3) δ = 7.49 - 7.43 (m, 1 H), 7.36 (d, J = 4.0 Hz, 5 H), 7.20 (d, J = 8.7
Hz, 1 H), 7.01 (d, J = 8.3 Hz, 1 H), 6.01 (br. s., 1 H), 5.08 (s, 1 H); 13C{1H} NMR (100 MHz,
CDCl3) δ = 152.3, 135.4, 131.2, 129.3, 128.6, 128.5, 127.6, 116.7, 110.7, 41.4; HRMS
(ESI-TOF) m/z: [M–H]– calcd for C14H9BrNO 285.9862; found 285.9876.
2-(6-hydroxy-[1,1'-biphenyl]-3-yl)-2-phenylacetonitrile (6c) :
Yellow gummy solid, 31 mg, 63% yield; Rf= 0.55 (petroleum ether/ethyl acetate = 80/20); 1H
NMR (200 MHz, CDCl3) δ = 7.53 - 7.41 (m, 5 H), 7.37 (s, 5 H), 7.23 (s, 1 H), 7.19 (d, J =
2.3 Hz, 1 H), 6.98 (d, J = 9.0 Hz, 1 H), 5.33 (s, 1 H), 5.12 (s, 1 H); 13C{1H} NMR (50 MHz,
CDCl3) δ = 152.4, 136.2, 136.1, 129.5, 129.4, 129.2, 129.0, 128.8, 128.5, 128.3, 128.2,
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128.2, 127.6, 119.8, 116.6, 41.9; HRMS (ESI-TOF) m/z: [M–H]– calcd for C20H14NO
4
5
284.1070; found 284.1081.
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7
4-(2-amino-1-phenylethyl)-2,6-di-tert-butylphenol (7) :
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9
Viscous yellow liquid, 35 mg, 69% yield; Rf= 0.55 (petroleum ether/ethyl acetate = 80/20);
1H NMR (400 MHz, CDCl3) δ = 7.32 - 7.24 (m, 4 H), 7.21 - 7.16 (m, 1 H), 7.03 (s, 2 H),
3.88 (t, J = 7.6 Hz, 1 H), 3.26 (d, J = 7.6 Hz, 2 H), 1.40 (s, 18 H); 13C{1H}NMR (100 MHz,
CDCl3) δ = 152.3, 143.2, 135.9, 133.0, 128.5, 128.1, 126.3, 124.4, 55.2, 47.5, 34.3, 30.3;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C22H32NO 326.2478; found 326.2480.
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■ AUTHOR INFORMATION
Corresponding Author
*E-mail: m.muthukrishnan@ncl.res.in
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
S.R.S. thank the Council of Scientific and Industrial Research (CSIR) -New Delhi for the
Junior Research Fellowship. Authors also thank CSIR-NCL for NMR support and for the
HRMS analysis.
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: http://pubs.acs.org
Copies of 1H, 13C and 19F NMR spectra of all the new compounds (PDF).
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(12) Selected examples: (a) Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders,
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intermolecular [3+2] cycloaddition between unactivated alkenes and in-situ generated para-
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(14) Selected examples: (a) Zhang, X.-Z.; Du, J.-Y.; Deng, Y.-H.; Chu, W.-D.; Yan, X.; Yu,
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