Catalytic C-H activation of phenylethylamines or benzylamines and their annulation with allenes

Article abstract of DOI:10.1021/jo501658s

Tetrahydro-3-benzazepines and tetrahydroisoquinolines are synthesized in one step from allenes and phenylethylamines or benzylamines, respectively. Mechanistically, it is assumed that activation of a C-H bond of an aromatic ring with Pd(II) occurs, directed by the primary amine, leading to the formation of a palladacycle into which an allene then undergoes insertion. The resulting π-allyl intermediate cyclizes to the products by an intramolecular allylic alkylation. The process is particularly useful with 2,3-butadienoates and amines having a quaternary carbon at the α-position. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501658s

Article
pubs.acs.org/joc
Catalytic C−H Activation of Phenylethylamines or Benzylamines and
Their Annulation with Allenes
Aleix Rodríguez,†,§ Joan Albert,‡,§ Xavier Ariza,*,†,§,∥ Jordi Garcia,*,†,§,∥ Jaume Granell,‡,§ Jaume Farras,†,§
̀
Andrea La Mela,† and Ernesto Nicolas†,§
́
†Departament de Química Organ
‡Departament de Química Inorgan
§Institut de Biomedicina de la Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
∥CIBER Fisiopatología de la Obesidad y la Nutricion
(CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain
̀
ica, Facultat de Química, Universitat de Barcelona, Martí i Franques
̀
1, 08028 Barcelona, Spain
̀
1, 08028 Barcelona, Spain
̀
ica, Facultat de Química, Universitat de Barcelona, Martí i Franques
́
S
* Supporting Information
ABSTRACT: Tetrahydro-3-benzazepines and tetrahydroiso-
quinolines are synthesized in one step from allenes and
phenylethylamines or benzylamines, respectively. Mechanisti-
cally, it is assumed that activation of a C−H bond of an
aromatic ring with Pd(II) occurs, directed by the primary
amine, leading to the formation of a palladacycle into which an
allene then undergoes insertion. The resulting π-allyl
intermediate cyclizes to the products by an intramolecular
allylic alkylation. The process is particularly useful with 2,3-
butadienoates and amines having a quaternary carbon at the α-position.
biological and pharmacological properties. This unique skeleton
INTRODUCTION
■
has also been found in several alkaloids.11
The use of allenes in the synthesis of highly functionalized
molecules has increased over the past few years.1 The 1,2-diene
moiety confers on allenes a unique reactivity that has been
applied in both organic and organometallic chemistry.2 In
particular, metal-catalyzed reactions of allenes have become a
useful tool for the formation of C−C and C−X bonds.3
However, transition-metal-catalyzed intermolecular reactions of
aromatic substrates with unactivated C−H bonds and allenes
has only recently been achieved with a variety of metals (Ir,4
Re,5 Pd,6 and mainly Rh7). In all cases a carbonyl-derived
directing group assists functionalization of the C−H bond
(Scheme 1).
In 2011 we first reported on the use of primary amines as
directing groups in C−H activation/carbonylation reactions
under Pd(II) catalysis.8 This result showed not only that the
amino group can act as a director/activator group as other
groups do but that it can also react further to form heterocyclic
structures. Consequently, we envisaged that this group could
also direct the carbopalladation of allenes through the
formation of a palladacycle (I).9 Since this carbopalladation
would provide a reactive π-allyl intermediate (II), then because
of its nucleophilic nature the amine would also undergo Tsuji−
Trost allylic alkylation to cyclize to a 3-benzazepine skeleton
(Scheme 2). Actually, it has been reported recently that the
stoichiometric insertion reaction of allenes into the Pd−C bond
of palladacycles of phenylethylamines (I) forms stable π-allyl
intermediates (II) that can decompose to tetrahydro-3-
benzapines under controlled conditions.10 Tetrahydro-3-
benzazepines are a family of compounds with interesting
RESULTS AND DISCUSSION
■
Since a metal-catalyzed method for their preparation is still
lacking, we initially investigated the proposed reaction under
conditions that were optimized for our carbonylation reaction.8
After a short optimization process, the use of acetic acid as the
solvent and benzoquinone (BQ) as the oxidant yielded optimal
results. Under these conditions, we tried the insertion of ethyl
2,3-butadienoate (1a) into α-quaternary primary amines 2 and
their expected cyclization to tetrahydro-3-benzazepines 3
(Scheme 3). As shown in Table 1 and in accordance with
our previous results for carbonylations,8 greater steric hindrance
at the quaternary carbon resulted in higher yields (see
comparison of entries 1−3 and also 4 and 5).12 Interestingly,
an electron-withdrawing group is necessary to obtain good
yields. Thus, replacement of a methyl group by a trifluor-
omethyl group resulted in a remarkably better yield (entries 5
and 6). It is also noteworthy that with this polarized allene, the
addition of the amino group to the nonsymmetrical π-allyl
intermediate is regioselective and only one regioisomer is
obtained. Furthermore, good Z stereoselectivities are usually
obtained (Table 1).13
Additionally, the cyclization process seems to be fast enough
to prevent the primary amine from activating the remaining
ortho C−H bond, thus preventing the formation of products
Received: July 22, 2014
© XXXX American Chemical Society
A
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Scheme 1. C−H Activation with Allene Insertion
Scheme 2. Carbopalladation of Allene Followed by Allylic
Alkylation
Scheme 4. Annulation of Allenes 1b−d with Amine 2a
a
b
c
Yield based on 4c used: 92%. Z olefin as the major isomer. Yield
based on 4d used: 72%.
Scheme 5. Synthesis of Tetrahydroisoquinolines by
Annulation of Benzylamines with Allenes
Scheme 3. Annulation of Allene 1a with α-Quaternary
Primary Amines
a
Table 1. Reaction of Allene 1a with Primary Amines 2
entry
amine
R
R′
Bn
product
yield
Z:E
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
CO2Me
CO2Me
CO2Me
Me
3a
3b
3c
3d
3e
3f
86%
76%
51%
13%
18%
73%
83%
83:17
90:10
82:18
>99:1
>99:1
87:13
83:17
Pr
allenes 1a and 1f under the same conditions, the corresponding
THIQs 6a and 6f were obtained in good yields as single regio-
and stereoisomers (Table 2, entries 1 and 6). However, when
other allenes were used, significant amounts of the other
regioisomer 7 were isolated (entries 2−5). The stereochemistry
of the double bond was mainly Z.13
Me
Me
Pr
Me
Pr
CF3
CO2Et
2g
CO2Et
3g
a
Reaction conditions: amine (1.0 equiv), allene (1.2 equiv),
The performance of amines 5b−d with allene 1a was also
explored (Scheme 6). The formation of tetrahydroisoquinolines
benzoquinone (1.1 equiv), and Pd(OAc)2 (5 mol %) in AcOH
(0.12 M) at 80 °C for 30 min.
a
Table 2. Annulation of Allenes 1a−f with Primary Amine 5a
derived from the incorportation of two allene molecules, a
common problem in some C−H activation protocols.
b
entry allene
R
yield
6:7
dr (7)
Z:E
Other less polarized allenes were also explored (Scheme 4).
Only with ethyl 3,4-pentadienoate (1b) were a high conversion
and yield of benzazepine 4b obtained. With other allenes (1c
and 1d) only low conversions were achieved. Again, only one
regioisomer was observed as a mixture of Z and E olefins.13
This approach could be also applied to the annulation of
benzylamines with allenes to form six-membered rings that
would provide access to tetrahydroisoquinolines (THIQs), a
common scaffold present in many biologically active com-
pounds (Scheme 5).14 When methyl α-propylphenylglycinate
(R′ = n-C3H7, R″ = CO2Me, 5a) reacted with conjugated
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
CO2Et
77%
95%
78%
53%
53%
68%
>99:1
34:66
47:53
40:60
34:66
>99:1
−
>99:1
87:13
88:12
>99:1
90:10
>99:1
CH2CO2Et
CH2OBn
Cy
72:28
73:27
70:30
80:20
−
CH2OTPS
CN
a
Reaction conditions: amine (1.0 equiv), allene (1.2 equiv for 1a−e
and 3.0 equiv for 1f), benzoquinone (1.1 equiv), and Pd(OAc)2 (5
mol %) in AcOH (0.12 M) at 80 °C for 30 min. Stereochemistry of
the double bond in 6.
b
B
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mixture of CuI (1.251 g, 6.58 mmol) and paraformaldehyde (1.012 g,
33.58 mmol) in dioxane (30 mL), and the mixture was heated at 100
°C for 4 h. The solvent was evaporated under reduced pressure, and
the resulting crude material was purified by flash column
chromatography (hexane/AcOEt 99:1) to obtain 1e as a colorless
Scheme 6. Annulation of Amines 5b−d with Allene 1a
1
oil (3.428 g, 11.114 mmol, 84%). Rf (hexane/AcOEt 9:1) = 0.55; H
NMR (400 MHz, CDCl3) δ 7.74−7.69 (m, 4H), 7.47−7.36 (m, 6H),
5.27 (quint, 1H, J = 6.4 Hz), 4.74 (dt, 2H, J = 6.5, 2.9 Hz), 4.25 (dt,
2H, J = 6.2, 2.9 Hz), 1.05 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
208.3, 135.7, 133.8, 129.8, 127.8, 90.8, 76.3, 62.1, 27.0, 26.7; IR (ATR,
cm−1) 2956, 2934, 2886, 2858, 1955, 1470, 1256, 1087, 776.
a
Estimated yield based on 8c used: 72%.
2-Methyl-1-phenylpentan-2-amine (2e). 2-Methyl-1-phenyl-
pentan-2-ol (9). Benzyl methyl ketone (2.003 g, 14.91 mmol) was
added dropwise to a 0.5 M solution of allylmagnesium bromide in
THF at 0 °C, and the mixture was stirred at 0 °C for 4 h. The reaction
was quenched by the addition of a saturated solution of NH4Cl, and
the aqueous phase was extracted with AcOEt. The combined organic
layer was washed with a saturated solution of NaCl, dried, and
evaporated under reduced pressure to obtain 2.60 g of a crude material
that was used in the next step without further purification. The crude
material (0.500 g) and Pt/C catalyst (0.222 g, 0.057 mmol) were
dissolved in AcOEt (25 mL). The suspension was flushed first with
nitrogen and then with hydrogen and was stirred for 1 h at rt. The
crude product was filtered through a short pad of Celite to obtain 9 as
a colorless oil (0.416 g, 2.33 mmol, 82%). Rf (hexane/AcOEt 4:1) =
0.41; 1H NMR (400 MHz, CDCl3) δ 7.34−7.20 (m, 5H), 2.79 (d, 1H,
J = 13.2 Hz), 2.73 (d, 1H, J = 13.2 Hz), 1.48−1.43 (m, 4H), 1.15 (s,
3H), 0.94 (t, 3H, J = 6.9 Hz); 13C NMR (101 MHz, CDCl3) δ 137.8,
130.7, 128.3, 126.5, 72.7, 48.2, 44.3, 26.6, 17.4, 14.8; HRMS (ESI+)
calcd for C12H22NO [M + NH4]+ 196.1696, found 196.1696.
also showed the trend that was observed with benzazepines: an
electron-withdrawing group at the α-position of the amine is
necessary for good yields.12
Finally, the relative rates of formation of six- and seven-
membered rings were evaluated using methyl α-benzylphenyl-
glycinate (5h) (Scheme 7). According to our previous work,8b
Scheme 7. Annulation of Allene 1a with Amine 5h
2-Chloro-N-(2-methyl-1-phenylpentan-2-yl)acetamide (10).
H2SO4 (0.57 mL, 10.10 mmol) was added dropwise to a solution of
9 (0.200 g, 1.12 mmol) and chloroacetonitrile (0.43 mL, 6.73 mmol)
in 0.5 mL of acetic acid at 0 °C. The mixture was stirred for 5 h at rt.
The mixture was poured into ice and extracted with CH2Cl2. The
combined organic layers were washed with a saturated solution of
Na2CO3 and brine and dried over anhydrous MgSO4, and the solvent
was removed under reduced pressure. The crude product was purified
by flash column chromatography (hexane/AcOEt 95:5) to obtain 10
as a colorless solid (0.165 g, 0.651 mmol, 58%). Rf (hexane/AcOEt
the five-membered-ring palladacycle is preferred over the six-
membered ring, and in this case it is also the more reactive one,
leading to THIQ 8h as the major product (87:13 Z/E
mixture).13
SUMMARY
1
4:1) = 0.41; H NMR (400 MHz, CDCl3) δ 7.32−7.21 (m, 3H),
■
7.15−7.11 (m, 2H), 6.10 (bs, 1H), 3.95 (s, 2H), 3.16 (d, 1H, J = 13.4
Hz), 2.93 (d, 1H, J = 13.4 Hz), 1.89 (ddd, 1H, J = 13.6, 12.0, 5.0 Hz),
1.57 (ddd, 1H, J = 13.6, 12.1, 4.8 Hz), 1.46−1.31 (m, 2H), 1.28 (s,
3H), 0.94 (t, 3H, J = 7.3 Hz); 13C NMR (101 MHz, CDCl3) δ 165.2,
137.3, 130.6, 128.2, 126.7, 57.4, 43.8, 43.1, 40.8, 24.1, 17.1, 14.5; IR
(ATR, cm−1) 3298, 2957, 2929, 1660, 1553, 1236, 702; HRMS (ESI+)
calcd for C14H21ClNO [M + H]+ 254.1306, found 254.1302.
2-Methyl-1-phenylpentan-2-amine (2e). A solution of 10 (0.124 g,
0.49 mmol) and thiourea (0.045 g, 0.59 mmol) in a mixture of ethanol
and acetic acid 5:1 (3 mL) was refluxed for 16 h. The reaction was
quenched by the addition of a 1 M solution of NaOH, and the mixture
was extracted with CH2Cl2. The organic layer was extracted with a 2 M
solution of HCl, and the aqueous layer was basicified with solid NaOH
and then extracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4, and the solvent was removed under
reduced pressure to obtain 2e as a colorless oil (0.070 g, 0.39 mmol,
80%). Rf (hexane/AcOEt 4:1) = 0.10; 1H NMR (400 MHz, CDCl3) δ
7.31−7.16 (m, 5H), 2.64 (s, 2H), 1.46−1.39 (m, 2H), 1.37−1.30 (m,
2H), 1.22 (bs, 2H), 1.03 (s, 3H), 0.93 (t, 3H, J = 7.0 Hz); 13C NMR
(101 MHz, CDCl3) δ 138.4, 130.6, 128.0, 126.3, 52.1, 49.3, 45.4, 27.8,
17.4, 14.8; HRMS (ESI+) calcd for C12H20N [M + H]+ 178.1590,
found 178.1591.
We have developed a new approach to 3-benzoazepine or
isoquinoline skeletons based on the reaction of terminal allenes
with phenylethylamines or benzylamines, respectively. Allenes
with an electron-withdrawing group such as an ester or nitrile
afforded good to excellent yields and stereoselectivities. On the
other hand, the amines need to be α-disubstituted, preferably
with electron-withdrawing groups.
EXPERIMENTAL SECTION
■
All of the reactants were obtained from commercial sources and used
as received. Solvents were distilled and dried before use. Column
chromatography was performed on silica gel (230−400 mesh).
Chemical shifts (δ) are given in parts per million and coupling
constants (J) in hertz. Amine 5b and allenes 1a and 1d are
commercially available. Amines 2a,8b 2b,8b 2c,8b 2d,8b 2g,18 5c,19
5d,8b and 5h8b and allenes 1b,15 1c,16 and 1f17 were prepared
according to previously published procedures.
(Buta-2,3-dien-1-yloxy)(tert-butyl)diphenylsilane (1e).
TBDPSCl (6.70 mL, 25.77 mmol) was added dropwise to a solution
of imidazole (2.340 g, 34.36 mmol) and propargyl alcohol (1.00 mL,
17.18 mmol) in anhydrous THF (30 mL). The resulting solution was
stirred at rt overnight, and the reaction was quenched by the addition
of a saturated solution of NH4Cl (15 mL). The phases were separated,
and the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4, and the solvent was
evaporated under reduced pressure to obtain 4.598 g of a crude oil that
was used in the next step without further purification. The crude oil
and dicyclohexylamine (4.71 mL, 23.67 mmol) were added to a
2-Benzyl-1,1,1-trifluoropentan-2-amine (2f). 1,1,1-Trifluoro-3-
phenylpropan-2-one Oxime (11). Trifluoromethyl benzyl ketone
(1.00 mL, 6.23 mmol) was added to a solution of hydroxylamine
hydrochloride (3.46 g, 49.79 mmol) and sodium acetate (4.09 g, 49.81
mmol) in a 5:1 water/ethanol mixture (25 mL), and the resulting
mixture was refluxed for 1 h. The mixture was cooled to rt and
extracted with CH2Cl2. The combined organic layers were dried over
C
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The Journal of Organic Chemistry
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anhydrous MgSO4, and the solvent was removed under reduced
pressure. The crude product was purified by flash column
chromatography (hexane/AcOEt 9:1) to obtain 11 as a colorless
solid (1.17 g, 5.76 mmol, 93%). mp = 38−40 °C (lit. 40−42 °C); Rf
(hexane/AcOEt 4:1) = 0.54; 1H NMR (400 MHz, CDCl3) δ 9.11 (bs,
1H), 7.33−7.22 (m, 5H), 3.87 (s, 2H); 13C NMR (101 MHz, CDCl3)
1H NMR (400 MHz, CDCl3) δ 7.40−7.15 (m, 7H), 7.11−7.06 (m,
2H), 5.93 (t, 1H, J = 2.5 Hz), 4.39 (dd, 1H, J = 20.5, 2.5 Hz), 4.19 (dd,
1H, J = 20.8, 2.5 Hz), 4.19 (q, 2H, J = 7.1 Hz), 3.62 (s, 3H), 3.16 (d,
1H, J = 14.2 Hz), 2.99 (d, 1H, J = 13.2 Hz), 2.97 (d, 1H, J = 14.2 Hz),
2.85 (d, 1H, J = 13.2 Hz), 1.88 (bs, 1H), 1.30 (t, 3H, J = 7.1 Hz); 13C
NMR (101 MHz, CDCl3) δ 175.1, 166.3, 164.8, 140.5, 136.1, 135.2,
130.1, 129.5, 129.2, 128.4, 127.9, 127.8, 127.1, 116.9, 66.4, 60.1, 52.0,
46.2, 43.4, 39.9, 14.5; IR (ATR, cm−1) 3402, 2979, 2950, 1732, 1704,
1615, 1169, 730; HRMS (ESI+) calcd for C23H26NO4 [M + H]+
380.1856, found 380.1860.
δ 149.2 (q, JCF = 31.9 Hz), 134.1, 129.1, 128.8, 127.2, 120.9 (q, JCF
=
274.6 Hz), 30.1; IR (ATR, cm−1) 3300, 3100, 2920, 1700, 1600, 1450;
HRMS (ESI+) calcd for C9H9F3NO [M + H]+ 204.0631, found
204.0633.
N-(2-Benzyl-1,1,1-trifluoropent-4-en-2-yl)hydroxylamine (12). A
1 M solution of allylmagnesium bromide in Et2O (4.90 mL, 0.98
mmol) was added to a solution of 11 (0.208 g, 0.98 mmol) in
anhydrous Et2O, and the resulting solution was stirred at rt for 4 h.
The reaction was quenched by the addition of a saturated solution of
NH4Cl, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried over anhydrous MgSO4, and the
solvent was removed under reduced pressure. The crude product was
purified by flash column chromatography (hexane/AcOEt 95:5) to
obtain 12 as a colorless oil (0.204 g, 0.832 mmol, 85%). Rf (hexane/
(E)-Methyl 2-Benzyl-5-(2-ethoxy-2-oxoethylidene)-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(E)-3a]. Compound (E)-
3a was obtained in 15% yield (0.021 g) as a colorless solid from 0.104
g of amine 2a, 0.053 g of allene 1a, 0.045 g of benzoquinone, 0.004 g
of Pd(OAc)2, and 3.5 mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.18;
1H NMR (400 MHz, CDCl3) δ 7.32−7.04 (m, 9H), 5.96 (s, 1H), 4.02
(q, 2H, J = 7.1 Hz), 3.77 (d, 1H, J = 1.5 Hz), 3.76 (d, 1H, J = 1.5 Hz),
3.63 (s, 3H), 3.18 (d, 1H, J = 14.2 Hz), 3.03 (d, 2H, J = 15.5 Hz), 2.86
(d, 1H, J = 14.1 Hz), 1.11 (t, 3H, J = 7.1 Hz).
(Z)-Methyl 5-(2-Ethoxy-2-oxoethylidene)-2-propyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(Z)-3b]. Compound (Z)-
3b was obtained in 68% yield (0.102 g) as a colorless oil from 0.100 g
of amine 2b, 0.064 g of allene 1a, 0.055 g of benzoquinone, 0.005 g of
1
AcOEt 4:1) = 0.44; H NMR (400 MHz, CDCl3) δ 7.35−7.23 (m,
5H), 5.85−5.72 (m, 1H), 5.27 (bs, 1H), 5.21−5.12 (m, 2H), 5.07 (bs,
1H), 3.26 (d, 1H, J = 14.0 Hz), 2.88 (d, 1H, J = 14.0 Hz), 2.44 (dd,
1H, J = 14.6, 7.2 Hz), 2.29 (dd, 1H, J = 14.6, 7.6 Hz); 13C NMR (101
MHz, CDCl3) δ 133.0 (q, JCF = 311.3 Hz), 131.0, 128.6, 128.3, 127.3,
127.2, 119.9, 66.0 (q, JCF = 22.8 Hz), 35.6 (q, JCF = 1.1 Hz), 35.5 (q,
JCF = 1.2 Hz); HRMS (ESI+) calcd for C12H15F3NO [M + H]+
246.1100, found 246.1108.
1
Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.63; H
NMR (400 MHz, CDCl3) δ 7.38−7.28 (m, 3H), 7.10−7.05 (m, 1H),
5.91 (t, 1H, J = 2.5 Hz), 4.34 (dd, 1H, J = 20.6, 2.5 Hz), 4.19 (q, 2H, J
= 7.2 Hz), 4.14 (dd, 1H, J = 21.0, 2.5 Hz), 3.75 (s, 3H), 3.10 (d, 1H, J
= 14.2 Hz), 2.85 (d, 1H, J = 14.2 Hz), 1.88 (bs, 1H), 1.66−1.56 (m,
1H), 1.56−1.46 (m, 1H), 1.31 (t, 3H, J = 7.1 Hz), 1.28−1.14 (m, 2H),
0.87 (t, 3H, J = 7.3 Hz); 13C NMR (101 MHz, CDCl3) δ 175.9, 166.3,
165.1, 140.2, 135.5, 129.4, 129.2, 127.9, 127.7, 116.9, 64.9, 60.1, 52.3,
46.4, 39.7, 21.2, 17.6, 14.5, 14.4; IR (ATR, cm−1) 3402, 2958, 1713,
1628, 1218, 1156, 1033, 731; HRMS (ESI+) calcd for C19H26NO4 [M
+ H]+ 332.1856, found 332.1860.
2-Benzyl-1,1,1-trifluoropentan-2-amine (2f). Pt/C catalyst (0.160
g, 0.82 mmol) was added to a solution of 12 (0.200 g, 0.81 mmol) in
AcOEt (25 mL). The resulting mixture was flushed first with nitrogen
and then with hydrogen and was stirred for 1 h at rt. The mixture was
filtered through a short pad of Celite to obtain 0.143 g of crude
material that was used in the next step without further purification.
The above crude material was added to a suspension of LiAlH4 (0.124
g, 3.108 mmol) in anhydrous THF (10 mL) under a nitrogen
atmosphere, and the mixture was stirred at rt for 48 h. The reaction
was quenched by the addition of methanol, and the solvent was
evaporated under reduced pressure. The crude material was
partitioned between CH2Cl2 and a 2 M solution of HCl. The aqueous
solution was extracted with CH2Cl2 and then basicified with solid
NaOH. The aqueous layer was extracted again with CH2Cl2, and the
combined organic layers were dried over anhydrous MgSO4 and
evaporated under reduced pressure to obtain 2f as a colorless oil
(0.046 g, 0.197 mmol, 38%). Rf (hexane/AcOEt 4:1) = 0.46; 1H NMR
(400 MHz, CDCl3) δ 7.40−7.22 (m, 5H), 2.89 (m, 2H), 1.59−1.41
(m, 4H), 1.37 (bs, 2H), 0.92 (t, 3H, J = 6.8 Hz); 13C NMR (101 MHz,
CDCl3) δ 135.5, 131.0, 128.3, 128.2 (q, JCF = 286.7 Hz), 127.1, 59.0
(q, JCF = 24.4 Hz), 40.1 (q, JCF = 1.4 Hz), 37.3, 16.8 (q, JCF = 1.4 Hz),
14.7; HRMS (ESI+) calcd for C12H17F3N [M + H]+ 232.1308, found
232.1309.
General Procedure for the Insertion Reaction. Acetic acid was
added to a mixture of the amine (1.0 equiv), the allene (1.2 equiv for
1a−e and 3.0 equiv for 1f), benzoquinone (1.1 equiv), and palladium
acetate (5 mol %) to a concentration of 0.12 M. The reaction mixture
was stirred for 30 min at 80 °C, and the crude material was filtered
through a short pad of Celite. Acetic acid was evaporated under
reduced pressure, and the crude material was dissolved in CH2Cl2 and
washed with a 1 M solution of NaOH, water, and brine. The organic
layer was dried over anhydrous MgSO4 and evaporated, and the
residue was purified by flash column chromatography. Complete
separation of 3a−c, 3f, 3g, and 4c stereoisomeric mixtures was not
accomplished, and only major stereoisomers were fully separated and
characterized; for minor stereoisomers, only 1H NMR data are
reported.
(E)-Methyl 5-(2-Ethoxy-2-oxoethylidene)-2-propyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(E)-3b]. Compound (E)-
3b was obtained in 8% yield (0.012 g) as a colorless oil from 0.100 g of
amine 2b, 0.064 g of allene 1a, 0.055 g of benzoquinone, 0.005 g of
1
Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.51; H
NMR (400 MHz, CDCl3) δ 7.31−7.04 (m, 4H), 5.94 (s, 1H), 4.02 (q,
2H, J = 7.1 Hz), 3.74 (m, 2H), 3.73 (s, 3H), 3.11 (d, 1H, J = 14.2 Hz),
2.88 (d, 1H, J = 14.2 Hz), 1.71−1.59 (m, 1H), 1.57−1.48 (m, 1H),
1.34−1.25 (m, 2H), 1.11 (t, 3H, J = 7.1 Hz), 0.87 (t, 3H, J = 7.3 Hz).
(Z)-Methyl 5-(2-Ethoxy-2-oxoethylidene)-2-methyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(Z)-3c]. Compound (Z)-
3c was obtained in 42% yield (0.066 g) as a colorless oil from 0.100 g
of amine 2c, 0.073 g of allene 1a, 0.063 g of benzoquinone, 0.006 g of
1
Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.27; H
NMR (400 MHz, CDCl3) δ 7.38−7.26 (m, 3H), 7.12−7.09 (m, 1H),
5.92 (t, 1H, J = 2.4 Hz), 4.34 (dd, 1H, J = 20.5, 2.5 Hz), 4.20 (q, 2H, J
= 7.1 Hz), 4.15 (dd, 1H, J = 20.5, 2.6 Hz), 3.77 (s, 3H), 3.17 (d, 1H, J
= 14.1 Hz), 2.79 (d, 1H, J = 14.1 Hz), 2.08 (bs, 1H), 1.31 (t, 3H, J =
7.1 Hz), 1.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 176.6, 166.3,
164.7, 140.1, 135.2, 129.6, 129.2, 127.9, 127.8, 117.0, 61.3, 60.1, 52.5,
46.6, 40.4, 24.6, 14.5; IR (ATR, cm−1) 3402, 2970, 1729, 1705, 1615,
1368, 1162, 1104, 728; HRMS (ESI+) calcd for C17H22NO4 [M + H]+
304.1543, found 304.1549.
(E)-Methyl 5-(2-Ethoxy-2-oxoethylidene)-2-methyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(E)-3c]. Compound (E)-
3c was obtained in 9% yield (0.014 g) as a colorless oil from 0.100 g of
amine 2c, 0.073 g of allene 1a, 0.063 g of benzoquinone, 0.006 g of
1
Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.12; H
NMR (400 MHz, CDCl3) δ 7.32−7.20 (m, 4H), 5.97 (s, 1H), 4.02 (q,
2H, J = 7.1 Hz), 3.76 (s, 3H), 3.75 (m, 2H), 3.18 (d, 1H, J = 14.2 Hz),
2.85 (d, 1H, J = 14.2 Hz), 1.31 (s, 3H), 1.11 (t, 3H, J = 7.1 Hz).
(Z)-Ethyl 2-(4,4-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-
1-ylidene)acetate (3d). Compound 3d was obtained in 13% yield
(0.022 g) as a brown oil from 0.102 g of amine 2d, 0.095 g of allene
1a, 0.081 g of benzoquinone, 0.008 g of Pd(OAc)2, and 5.0 mL of
AcOH. Rf (hexane/AcOEt 7:3) = 0.12; 1H NMR (400 MHz, CDCl3)
(Z)-Methyl 2-Benzyl-5-(2-ethoxy-2-oxoethylidene)-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(Z)-3a]. Compound (Z)-
3a was obtained in 71% yield (0.104 g) as a colorless solid from 0.104
g of amine 2a, 0.053 g of allene 1a, 0.045 g of benzoquinone, 0.004 g
of Pd(OAc)2, and 3.5 mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.31;
D
dx.doi.org/10.1021/jo501658s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
δ 7.37−7.27 (m, 3H), 7.08 (d, 1H, J = 7.3 Hz), 5.90 (t, 1H, J = 2.4
Hz), 4.25 (d, 2H, J = 2.2 Hz), 4.21 (q, 2H, J = 7.2 Hz), 2.62 (s, 2H),
2.19 (bs, 1H), 1.31 (t, 3H, J = 7.1 Hz), 1.13 (s, 6H); 13C NMR (101
MHz, CDCl3) δ 166.4, 139.4, 137.1, 129.6, 129.3, 128.6, 128.1, 127.3,
117.0, 60.1, 52.3, 45.2, 45.0, 27.5, 14.5; HRMS (ESI+) calcd for
C16H22NO2 [M + H]+ 260.1645, found 260.1646.
(Z)-Ethyl 2-(4-Methyl-4-propyl-2,3,4,5-tetrahydro-1H-benzo[d]-
azepin-1-ylidene)acetate (3e). Compound 3e was obtained in 18%
yield (0.020 g) as a colorless oil from 0.070 g of amine 2e, 0.056 g of
allene 1a, 0.049 g of benzoquinone, 0.005 g of Pd(OAc)2, and 3.5 mL
of AcOH. Rf (hexane/AcOEt 7:3) = 0.26; 1H NMR (400 MHz,
CDCl3) δ 7.29−7.17 (m, 3H), 7.02−6.94 (m, 1H), 5.82 (t, 1H, J = 2.5
Hz), 4.19−4.15 (m, 2H), 4.13 (q, 2H, J = 7.1 Hz), 2.57 (d, 1H, J =
13.6 Hz), 2.48 (d, 1H, J = 13.6 Hz), 1.54 (bs, 1H), 1.33−1.27 (m,
4H), 1.24 (t, 3H, J = 7.1 Hz), 0.95 (s, 3H), 0.85 (t, 3H, J = 6.2 Hz);
13C NMR (101 MHz, CDCl3) δ 167.0, 166.4, 139.7, 137.0, 130.0,
Pd(OAc)2, and 3.5 mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.20; H
NMR (400 MHz, CDCl3) δ 7.37−7.32 (m, 1H), 7.29−7.21 (m, 5H),
7.16−7.11 (m, 1H), 7.10−7.05 (m, 2H), 5.77 (tt, 1H, J = 7.1, 2.4 Hz),
4.16 (q, 2H, J = 7.2 Hz), 3.80−3.67 (m, 2H), 3.65 (s, 3H), 3.15−3.13
(m, 3H), 2.99 (t, 2H, J = 13.1 Hz), 2.83 (d, 1H, J = 13.2 Hz), 1.88 (bs,
1H), 1.27 (t, 3H, J = 7.0 Hz); 13C NMR (101 MHz, CDCl3) δ 175.5,
171.5, 144.9, 141.7, 136.3, 134.2, 130.1, 129.4, 128.3, 127.9, 127.6,
127.5, 127.0, 119.6, 65.8, 60.9, 52.0, 44.3, 43.9, 40.3, 33.6, 14.4; HRMS
(ESI+) calcd for C24H28NO4 [M + H]+ 394.2013, found 394.2012.
(E)-Methyl 2-Benzyl-5-(3-ethoxy-3-oxopropylidene)-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(E)-4b]. Compound (E)-
4b was obtained in 44% yield (0.064 g) as a yellow oil from 0.102 g of
amine 2a, 0.056 g of allene 1b, 0.045 g of benzoquinone, 0.004 g of
1
Pd(OAc)2, and 3.5 mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.16; H
NMR (400 MHz, CDCl3) δ 7.31−7.13 (m, 9H), 5.81 (t, 1H, J = 7.4
Hz), 4.12 (q, 2H, J = 7.1 Hz), 3.69−3.65 (m, 2H), 3.60 (s, 3H), 3.37
(d, 1H, J = 13.1 Hz), 3.18 (d, 1H, J = 13.1 Hz), 3.09 (d, 2H, J = 7.4
Hz), 2.88 (d, J = 13.1 Hz), 2.85 (d, 1H, J = 13.1 Hz), 1.77 (bs, 1H),
1.24 (t, 3H, J = 6.3 Hz); 13C NMR (101 MHz, CDCl3) δ 172.1, 171.2,
144.4, 138.8, 136.3, 136.1, 135.7, 130.1, 130.0, 128.7, 128.6, 127.2,
127.1, 119.2, 64.9, 60.5, 51.9, 51.7, 46.5, 44.9, 34.8, 14.3; HRMS (ESI
+) calcd for C24H28NO4 [M + H]+ 394.2013, found 394.2011.
(Z)-Methyl 2-Benzyl-5-(2-(benzyloxy)ethylidene)-2,3,4,5-tetrahy-
dro-1H-benzo[d]azepine-2-carboxylate [(Z)-4c]. Compound 4c was
obtained in 27% yield (0.043 g) as a yellow oil from 0.104 g of amine
2a, 0.071 g of allene 1c, 0.045 g of benzoquinone, 0.004 g of
129.2, 128.0, 127.2, 116.8, 77.2, 60.0, 54.7, 44.7, 44.0, 42.1, 24.3, 17.3,
14.9, 14.5; IR (ATR, cm−1) 3402, 2957, 2930, 2871, 1706, 1162;
HRMS (ESI+) calcd for C18H26NO2 [M + H]+ 288.1958, found
288.1957.
(Z)-Ethyl 2-(4-Propyl-4-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-1-ylidene)acetate [(Z)-3f]. Compound (Z)-3f was
obtained in 64% yield (0.094 g) as a colorless oil from 0.101 g of
amine 2f, 0.061 g of allene 1a, 0.053 g of benzoquinone, 0.005 g of
1
Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 9:1) = 0.33; H
NMR (400 MHz, CDCl3) δ 7.41−7.29 (m, 3H), 7.16−7.10 (m, 1H),
5.90 (t, 1H, J = 2.5 Hz), 4.53 (dd, 1H, J = 20.8, 1.8 Hz), 4.39 (dd, 1H,
J = 20.8, 2.5 Hz), 4.20 (q, 2H, J = 7.1 Hz), 3.21 (d, 1H, J = 14.1 Hz),
2.72 (d, 1H, J = 14.1 Hz), 1.58 (bs, 1H), 1.48−1.35 (m, 4H), 1.31 (t,
3H, J = 7.1 Hz), 0.84 (t, 3H, J = 6.1 Hz); 13C NMR (101 MHz,
1
Pd(OAc)2, and 3.5 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.45; H
NMR (400 MHz, CDCl3) δ 7.39−7.32 (m, 4H), 7.31−7.20 (m, 7H),
7.16−7.04 (m, 3H), 5.78 (t, 1H, J = 6.2 Hz), 4.56 (s, 2H), 4.15 (d, 2H,
J = 6.0 Hz), 3.73 (d, 1H, J = 18.2 Hz), 3.64 (s, 3H), 3.63 (d, 1H, J =
18.2 Hz), 3.16 (d, 1H, J = 14.1 Hz), 3.00 (d, 1H, J = 13.1 Hz), 2.98 (d,
1H, J = 14.1 Hz), 2.81 (d, 1H, J = 13.2 Hz), 2.05 (bs, 1H); 13C NMR
(101 MHz, CDCl3) δ 175.4, 144.9, 141.5, 138.3, 136.3, 134.3, 130.0,
129.4, 128.6, 128.3, 127.9, 127.8, 127.6, 127.6, 127.0, 124.8, 72.6, 66.2,
65.9, 51.9, 44.0, 43.9, 40.4; HRMS (ESI+) calcd for C28H30NO3 [M +
H]+ 428.2220, found 428.2221.
(E)-Methyl 2-Benzyl-5-(2-(benzyloxy)ethylidene)-2,3,4,5-tetrahy-
dro-1H-benzo[d]azepine-2-carboxylate [(E)-4c]. Compound (E)-4c
was obtained in 8% yield (0.013 g) as a yellow oil from 0.104 g of
amine 2a, 0.071 g of allene 1c, 0.045 g of benzoquinone, 0.004 g of
CDCl3) δ 166.2, 164.6, 139.9, 134.5, 130.2, 129.4, 128.5 (q, JCF
=
289.7 Hz), 128.2, 127.9, 117.4, 61.1 (q, JCF = 23.8 Hz), 60.2, 45.7,
37.5, 35.9, 16.8 (q, JCF = 1.9 Hz), 14.7, 14.5; IR (ATR, cm−1) 3402,
2966, 2875, 1703, 1613, 1369, 1140, 1111, 768; HRMS (ESI+) calcd
for C18H23F3NO2 [M + H]+ 342.1675, found 342.1676.
(E)-Ethyl 2-(4-Propyl-4-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-1-ylidene)acetate [(E)-3f]. Compound (E)-3f was
obtained in 9% yield (0.013 g) as a colorless oil from 0.101 g of amine
2f, 0.061 g of allene 1a, 0.053 g of benzoquinone, 0.005 g of
1
Pd(OAc)2, and 4.0 mL of AcOH. H NMR (400 MHz, CDCl3) δ
1
Pd(OAc)2, and 3.5 mL of AcOH. H NMR (400 MHz, CDCl3) δ
7.33−7.22 (m, 3H), 7.16−7.13 (m, 1H), 5.98 (t, 1H, J = 1.8 Hz), 4.01
(q, 2H, J = 7.1 Hz), 3.95 (d, 1H, J = 17.9 Hz), 3.75 (d, 1H, J = 17.9
Hz), 3.24 (d, 1H, J = 14.2 Hz), 2.70 (d, 1H, J = 14.2 Hz), 1.45−1.40
(m, 2H), 1.31−1.25 (m, 2H), 1.10 (t, 3H, J = 7.1 Hz), 0.86 (t, 3H, J =
6.2 Hz).
7.30−7.22 (m, 10H), 7.18−7.15 (m, 4H), 5.84 (t, 1H, J = 7.0 Hz),
4.43 (s, 2H), 4.01 (m, 2H), 3.71 (m, 2H), 3.60 (s, 3H), 3.18 (d, 1H, J
= 14.0 Hz), 3.02 (d, 1H, J = 14.0 Hz), 3.01 (d, 1H, J = 13.2 Hz), 2.86
(d, 1H, J = 13.2 Hz).
(Z)-Methyl 2-Benzyl-5-(cyclohexylmethylene)-2,3,4,5-tetrahydro-
1H-benzo[d]azepine-2-carboxylate (4d). Compound 4d was ob-
tained in 32% yield (0.052 g) as a yellow oil from 0.113 g of amine 2a,
0.065 g of allene 1d, 0.055 g of benzoquinone, 0.005 g of Pd(OAc)2,
(Z)-Diethyl 5-(2-Ethoxy-2-oxoethylidene)-4,5-dihydro-1H-benzo-
[d]azepine-2,2(3H)-dicarboxylate [(Z)-3g]. Compound (Z)-3g was
obtained in 69% yield (0.049 g) as a colorless oil from 0.060 g of
amine 2g, 0.032 g of allene 1a, 0.027 g of benzoquinone, 0.003 g of
1
1
and 4.0 mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.60; H NMR (400
Pd(OAc)2, and 2.0 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.14; H
MHz, CDCl3) δ 7.31 (dd, 1H, J = 7.4, 1.4 Hz), 7.28−7.17 (m, 5H),
7.15−7.06 (m, 3H), 5.41 (dt, 1H, J = 9.6, 2.2 Hz), 3.81 (dd, 1H, J =
17.7, 2.3 Hz), 3.69 (dd, 1H, J = 17.6, 2.4 Hz), 3.65 (s, 3H), 3.16 (d,
1H, J = 14.0 Hz), 3.00 (d, 1H, J = 13.2 Hz), 2.97 (d, 1H, J = 14.0 Hz),
2.82 (d, 1H, J = 13.2 Hz), 2.29−2.17 (m, 1H), 1.90 (bs, 1H), 1.80−
1.62 (m, 4H), 1.37−1.04 (m, 6H); 13C NMR (101 MHz, CDCl3) δ
175.7, 142.6, 139.6, 136.4, 135.1, 134.1, 130.1, 129.4, 128.3, 127.8,
127.5, 127.0, 126.9, 65.9, 51.9, 44.0, 43.8, 40.4, 36.9, 32.8, 32.7, 26.2,
26.1, 26.0; IR (ATR, cm−1) 3402, 2920, 2848, 1731, 1448, 1216, 1175,
908, 730; HRMS (ESI+) calcd for C26H32NO2 [M + H]+ 390.2428,
found 390.2427.
NMR (400 MHz, CDCl3) δ 7.36−7.32 (m, 1H), 7.30−7.25 (m, 2H),
7.12−7.08 (m, 1H), 5.91 (t, 1H, J = 2.5 Hz), 4.32 (d, 2H, J = 2.5 Hz),
4.29−4.15 (m, 6H), 3.34 (s, 2H), 1.30 (t, 3H, J = 7.1 Hz), 1.26 (t, 6H,
J = 7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 169.7, 166.2, 164.2,
139.9, 134.2, 129.4, 129.4, 128.0, 128.0, 117.3, 69.3, 62.2, 60.1, 45.7,
37.1, 14.4, 14.2; IR (ATR, cm−1) 3401, 2980, 2934, 1730, 1705, 1615,
1282, 1167; HRMS (ESI+) calcd for C20H26NO6 [M + H]+ 376.1755,
found 376.1760.
(E)-Diethyl 5-(2-Ethoxy-2-oxoethylidene)-4,5-dihydro-1H-benzo-
[d]azepine-2,2(3H)-dicarboxylate [(E)-3g]. Compound (E)-3g was
obtained in 14% yield (0.010 g) as a colorless oil from 0.60 g of amine
2g, 0.032 g of allene 1a, 0.027 g of benzoquinone, 0.003 g of
(Z)-Methyl 4-(2-Ethoxy-2-oxoethylidene)-1-propyl-1,2,3,4-tetra-
hydroisoquinoline-1-carboxylate (6a). Compound 6a was obtained
in 77% yield (0.118 g) as a yellow oil from 0.100 g of amine 5a, 0.065
g of allene 1a, 0.057 g of benzoquinone, 0.004 g of Pd(OAc)2, and 4.0
1
Pd(OAc)2, and 2.0 mL of AcOH. H NMR (400 MHz, CDCl3) δ
7.28−7.10 (m, 4H), 5.94 (t, 1H, J = 1.7 Hz), 4.25 (q, 2H, J = 7.1 Hz),
4.21 (q, 2H, J = 7.1 Hz), 4.02 (q, 2H, J = 7.1 Hz), 3.83 (m, 2H), 3.38
(s, 2H), 1.28 (t, 6H, J = 7.1 Hz), 1.11 (t, 3H, J = 7.1 Hz).
1
mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.22; H NMR (400 MHz,
CDCl3) δ 7.66 (d, 1H, J = 8.0 Hz), 7.52−7.44 (m, 1H), 7.40−7.32 (m,
1H), 7.31−7.26 (m, 1H), 6.33 (t, 1H, J = 1.6 Hz), 4.51 (dd, 1H, J =
17.2, 1.5 Hz), 4.27 (dd, 1H, J = 17.2, 1.9 Hz), 4.21 (q, 2H, J = 7.1 Hz),
3.74 (s, 3H), 2.13−2.04 (m, 1H), 1.97−1.88 (m, 1H), 1.38−1.24 (m,
(Z)-Methyl 2-Benzyl-5-(3-ethoxy-3-oxopropylidene)-2,3,4,5-tetra-
hydro-1H-benzo[d]azepine-2-carboxylate [(Z)-4b]. Compound (Z)-
4b was obtained in 43% yield (0.063 g) as a yellow oil from 0.102 g of
amine 2a, 0.056 g of allene 1b, 0.045 g of benzoquinone, 0.004 g of
E
dx.doi.org/10.1021/jo501658s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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2H), 1.32 (t, 3H, J = 7.1 Hz), 0.91 (t, 3H, J = 7.3 Hz); 13C NMR (101
MHz, CDCl3) δ 174.1, 166.5, 150.5, 139.0, 132.0, 129.9, 127.5, 126.8,
124.9, 111.5, 64.6, 60.0, 52.6, 42.4, 41.3, 17.6, 14.3, 14.2; IR (ATR,
cm−1) 3402, 2958, 2930, 2872, 1727, 1705, 1620, 1221, 1172, 1154,
729; HRMS (ESI+) calcd for C18H24NO4 [M + H]+ 318.1700, found
318.1694.
(ddd, 1H, J = 14.1, 11.7, 4.4 Hz), 1.82 (ddd, 1H, J = 14.1, 12.0, 4.6
Hz), 1.48−1.38 (m, 1H), 1.34−1.25 (m, 1H), 0.86 (t, 3H, J = 7.4 Hz);
13C NMR (101 MHz, CDCl3) δ 174.1, 141.8, 138.3, 137.7, 134.0,
128.5, 128.0, 127.8, 127.7, 127.5, 125.7, 125.3, 107.9, 77.2, 73.5, 72.6,
65.5, 52.7, 52.6, 41.0, 18.4, 14.4; IR (ATR, cm−1) 3402, 2954, 2859,
1731, 1428, 1395, 1220, 760; HRMS (ESI+) calcd for C23H28NO3 [M
+ H]+ 366.2064, found 366.2060.
(Z)-Methyl 4-(Cyclohexylmethylene)-1-propyl-1,2,3,4-tetrahydroi-
soquinoline-1-carboxylate (6d). Compound 6d was obtained in 21%
yield (0.033 g) as a brown oil from 0.103 g of amine 5a, 0.073 g of
allene 1d, 0.058 g of benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL
of AcOH. Rf (hexane/AcOEt 4:1) = 0.45; 1H NMR (400 MHz,
CDCl3) δ 7.60−7.55 (m, 1H), 7.43−7.39 (m, 1H), 7.22−7.17 (m,
2H), 5.87 (d, 1H, J = 9.2 Hz), 3.76 (s, 2H), 3.72 (s, 3H), 3.00 (bs,
1H), 2.37−2.28 (m, 1H), 2.15−2.06 (m, 1H), 2.00−1.86 (m, 1H),
1.80−1.64 (m, 4H), 1.43−1.11 (m, 8H), 0.91 (t, 3H, J = 7.3 Hz); 13C
NMR (101 MHz, CDCl3) δ 174.8, 135.9, 134.6, 130.1, 129.5, 127.2,
126.9, 126.8, 123.7, 65.1, 52.6, 41.9, 41.5, 37.0, 33.4, 33.3, 26.1, 26.0,
26.0, 17.6, 14.4; IR (ATR, cm−1) 3403, 2933, 2860, 1738, 1563, 1355,
1237; HRMS (ESI+) calcd for C21H30NO2 [M + H]+ 328.2271, found
328.2275.
Methyl 4-(3-Ethoxy-3-oxopropylidene)-1-propyl-1,2,3,4-tetrahy-
droisoquinoline-1-carboxylate (6b). Compound 6b was obtained as
an 87:13 Z:E mixture of stereoisomers in 32% yield (0.051 g) as a
brown oil from 0.102 g of amine 5a, 0.073 g of allene 1b, 0.057 g of
benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL of AcOH. Rf
1
(hexane/AcOEt 7:3) = 0.17; H NMR (400 MHz, CDCl3) δ 7.61
(m, 1H), 7.42 (m, 1H), 7.23 (m, 2H), 6.19 (t, 1H, J = 7.3 Hz), 4.18 (q,
2H, J = 7.1 Hz), 3.73 (m, 2H), 3.71 (s, 3H), 3.23 (dd, 2H, J = 7.3, 2.2
Hz), 2.80 (bs, 1H), 2.10 (m, 1H), 1.91 (m, 1H), 1.31 (m, 2H), 1.27 (t,
3H, J = 7.1 Hz), 0.90 (t, 3H, J = 7.4 Hz); 13C NMR (101 MHz,
CDCl3) δ 174.7, 171.6, 136.3, 134.4, 133.7, 127.5, 127.4, 126.9, 124.1,
114.6, 65.0, 61.0, 52.6, 42.0, 41.8, 33.6, 17.6, 14.4, 14.4; HRMS (ESI+)
calcd for C19H26NO4 [M + H]+ 332.1856, found 332.1849.
Methyl 3-(2-Ethoxy-2-oxoethyl)-4-methylene-1-propyl-1,2,3,4-
tetrahydroisoquinoline-1-carboxylate (7b-A). Diastereoisomer A of
compound 7b was obtained in 50% yield (0.080 g) as a brown oil from
0.102 g of amine 5a, 0.073 g of allene 1b, 0.057 g of benzoquinone,
0.006 g of Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) =
Methyl 3-Cyclohexyl-4-methylene-1-propyl-1,2,3,4-tetrahydroi-
soquinoline-1-carboxylate (7d). Compound 7d was obtained as a
7:3 mixture of diastereoisomers in 32% yield (0.051 g) as a brown oil
from 0.103 g of amine 5a, 0.073 g of allene 1d, 0.058 g of
benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL of AcOH. Rf
1
0.53; H NMR (400 MHz, CDCl3) δ 7.52−7.41 (m, 2H), 7.26−7.20
(m, 2H), 5.42 (d, 1H, J = 1.0 Hz), 4.94 (d, 1H, J = 1.0 Hz), 4.16 (m,
2H), 3.94 (m, 1H), 3.72 (s, 3H), 2.82 (dd, 1H, J = 15.1, 5.2 Hz), 2.64
(dd, 1H, J = 15.1, 8.6 Hz), 2.56 (bs, 1H), 2.11 (ddd, 1H, J = 14.0, 11.7,
4.4 Hz), 1.89 (ddd, 1H, J = 14.0, 12.0, 4.5 Hz), 1.58−1.45 (m, 2H),
1.26 (t, 3H, J = 7.1 Hz), 0.90 (t, 3H, J = 7.4 Hz); 13C NMR (101
MHz, CDCl3) δ 174.2, 172.0, 143.8, 137.2, 134.2, 128.3, 127.5, 126.3,
125.4, 105.8, 65.6, 60.7, 52.8, 49.8, 41.5, 39.0, 18.3, 14.4, 14.3; HRMS
(ESI+) calcd for C19H26NO4 [M + H]+ 332.1856, found 332.1848.
Methyl 3-(2-Ethoxy-2-oxoethyl)-4-methylene-1-propyl-1,2,3,4-
tetrahydroisoquinoline-1-carboxylate (7b-B). Diastereoisomer B of
compound 7b was obtained in 13% yield (0.021 g) as a brown oil from
0.102 g of amine 5a, 0.073 g of allene 1b, 0.057 g of benzoquinone,
0.006 g of Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) =
1
(hexane/AcOEt 4:1) = 0.64; H NMR (400 MHz, CDCl3) δ 7.51−
7.43 (m, 1H), 7.30−7.20 (m, 3H), 5.44 (s, 0.7H), 5.40 (s, 0.3H), 4.97
(s, 1H), 3.76 (s, 2.1H), 3.62 (s, 0.9H), 3.60 (d, 0.3H, J = 5.4 Hz), 3.28
(d, 0.7H, J = 5.6 Hz), 2.17 (bs, 1H), 2.09−1.02 (m, 15H), 0.94 (t,
0.9H, J = 7.3 Hz), 0.87 (t, 2.1H, J = 7.4 Hz); 13C NMR (101 MHz,
CDCl3) δ 175.8, 174.7, 143.7, 137.9, 136.3, 135.3, 127.8, 127.6, 127.5,
127.4, 126.4, 125.8, 125.5, 125.0, 109.2, 107.9, 65.2, 64.7, 60.4, 59.0,
52.6, 52.4, 42.2, 42.1, 41.1, 40.1, 31.1, 30.6, 28.5, 28.0, 26.8, 26.8, 26.7,
26.7, 26.6, 18.2, 17.2, 14.5, 14.4. IR (ATR, cm−1) 3404, 2930, 2862,
1738, 1568, 1342, 1221; HRMS (ESI+) calcd for C21H30NO2 [M +
H]+ 328.2271, found 328.2274.
Methyl 4-(2-((tert-Butyldiphenylsilyl)oxy)ethylidene)-1-propyl-
1,2,3,4-tetrahydroisoquinoline-1-carboxylate (6e). Compound 6e
was obtained as a 90:10 Z:E mixture of stereoisomers in 18% yield
(0.045 g) as a brown oil from 0.105 g of amine 5a, 0.179 g of allene 1e,
0.059 g of benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL of AcOH.
1
0.49; H NMR (400 MHz, CDCl3) δ 7.52 (m, 2H), 7.32−7.21 (m,
2H), 5.49 (d, 1H, J = 1.0 Hz), 4.95 (d, 1H, J = 1.0 Hz), 4.20 (q, 2H, J
= 7.1 Hz), 4.13 (m, 1H), 3.69 (s, 3H), 2.87 (dd, 1H, J = 15.2, 4.6 Hz),
2.63 (dd, 1H, J = 15.2, 8.2 Hz), 2.10 (m, 1H), 1.96 (m, 1H), 1.28 (t,
3H, J = 7.1 Hz), 1.30−1.15 (m, 2H), 0.88 (t, 3H, J = 7.3 Hz); 13C
NMR (101 MHz, CDCl3) δ 175.4, 172.2, 143.6, 135.7, 134.5, 128.0,
127.5, 127.3, 124.8, 106.6, 65.2, 60.8, 52.6, 51.3, 43.3, 39.1, 17.0, 14.4,
14.3; HRMS (ESI+) calcd for C19H26NO4 [M + H]+ 332.1856, found
332.1847.
1
Rf (hexane/AcOEt 4:1) = 0.35; H NMR (400 MHz, CDCl3) δ 7.72
(dd, 4H, J = 7.8, 1.6 Hz), 7.59−7.53 (m, 1H), 7.45−7.37 (m, 7H),
7.25−7.21 (m, 2H), 6.18 (t, 0.95H, J = 6.3 Hz), 5.71 (t, 0.05H, J = 6.4
Hz), 4.51 (d, 0.1H, J = 6.3 Hz), 4.42 (dd, 1.9H, J = 6.2, 2.4 Hz), 3.71
(s, 2.85H), 3.69 (s, 0.15H), 3.53 (d, 2H, J = 6.6 Hz), 2.08 (ddd, 1H, J
= 14.0, 11.6, 4.8 Hz), 1.89 (ddd, 1H, J = 14.0, 11.8, 4.9 Hz), 1.37−1.29
(m, 2H), 1.07 (s, 9H), 0.90 (t, 3H, J = 7.4 Hz); 13C NMR (101 MHz,
CDCl3) δ 174.6, 136.6, 135.7, 135.7, 133.8, 133.8, 133.7, 132.3, 129.8,
129.8, 127.8, 127.8, 127.8, 127.8, 127.5, 127.3, 126.8, 124.2, 122.6,
77.2, 64.9, 60.9, 52.6, 41.9, 41.4, 27.0, 19.3, 17.7, 14.4; IR (ATR, cm−1)
3402, 2956, 2929, 2855, 1728, 1427, 1219, 1110, 700; HRMS (ESI+)
calcd for C32H40NO3Si [M + H]+ 514.2772, found 514.2781.
Methyl 3-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-methylene-1-
propyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (7e). Com-
pound 7e was obtained as a 4:1 mixture of diastereoisomers in 35%
yield (0.087 g) as a brown oil from 0.105 g of amine 5a, 0.179 g of
allene 1e, 0.059 g of benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL
of AcOH. Rf (hexane/AcOEt 4:1) = 0.54; 1H NMR (400 MHz,
CDCl3) δ 7.77−7.66 (m, 4H), 7.59−7.54 (m, 1H), 7.47−7.21 (m,
9H), 5.55 (d, 0.8H, J = 1.3 Hz), 5.48 (d, 0.2H, J = 1.4 Hz), 5.08 (d,
0.8H, J = 1.4 Hz), 4.78 (d, 0.2H, J = 1.4 Hz), 4.14 (dd, 0.4H, J = 5.5,
1.6 Hz), 4.01 (dd, 1.6H, J = 4.5, 1.1 Hz), 3.75 (s, 2.4H), 3.70 (s, 0.6H),
3.68 (dd, 1H, J = 5.1, 3.8 Hz), 2.11 (ddd, 1H, J = 13.9, 11.6, 4.3 Hz),
1.85 (ddd, 1H, J = 14.1, 11.9, 4.5 Hz), 1.59−1.47 (m, 1H), 1.41−1.32
(m, 1H), 1.02 (s, 9H), 0.91 (t, 3H, J = 7.4 Hz); 13C NMR (101 MHz,
CDCl3) δ 174.0, 142.2, 138.2, 135.8, 135.8, 135.8, 135.7, 134.9, 134.4,
133.6, 133.5, 129.8, 129.8, 127.9, 127.8, 127.8, 127.7, 127.6, 127.4,
127.3, 125.3, 125.2, 124.2, 108.2, 106.8, 77.2, 66.6, 66.4, 65.6, 64.9,
Methyl 4-(2-(Benzyloxy)ethylidene)-1-propyl-1,2,3,4-tetrahydroi-
soquinoline-1-carboxylate (6c). Compound 6c was obtained as an
88:12 Z:E mixture of stereoisomers in 37% yield (0.065 g) as a brown
oil from 0.100 g of amine 5a, 0.093 g of allene 1c, 0.059 g of
benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL of AcOH. Rf
1
(hexane/AcOEt 4:1) = 0.09; H NMR (400 MHz, CDCl3) δ 7.63−
7.59 (m, 1H), 7.46−7.42 (m, 1H), 7.38−7.19 (m, 7H), 6.20 (t, 0.88H,
J = 6.6 Hz), 5.72 (t, 0.12H, J = 6.6 Hz), 4.56 (s, 2H), 4.31 (d, 0.24H, J
= 6.6 Hz), 4.23 (dd, 1.76H, J = 6.6, 2.1 Hz), 3.72 (s, 3H), 3.71 (d, 2H,
J = 3.5 Hz), 2.10 (bs, 1H), 2.10 (ddd, 1H, J = 14.1, 11.5, 5.1 Hz), 1.92
(ddd, 1H, J = 14.0, 11.7, 5.0 Hz), 1.37−1.28 (m, 2H), 0.90 (t, 3H, J =
7.4 Hz); 13C NMR (101 MHz, CDCl3) δ 174.7, 138.2, 136.5, 134.8,
133.5, 128.5, 127.9, 127.8, 127.7, 127.3, 126.9, 124.2, 119.4, 72.5, 66.3,
65.0, 52.6, 42.0, 41.6, 17.6, 14.4; IR (ATR, cm−1) 3402, 2956, 2870,
1728, 1455, 1364, 1217, 734; HRMS (ESI+) calcd for C23H28NO3 [M
+ H]+ 366.2064, found 366.2065.
Methyl 3-((Benzyloxy)methyl)-4-methylene-1-propyl-1,2,3,4-tet-
rahydroisoquinoline-1-carboxylate (7c). Compound 7c was obtained
in 41% yield (0.072 g) as a yellow oil from 0.100 g of amine 5a, 0.093
g of allene 1c, 0.059 g of benzoquinone, 0.006 g of Pd(OAc)2, and 4.0
1
mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.28; H NMR (400 MHz,
CDCl3) δ 7.55−7.47 (m, 2H), 7.32−7.15 (m, 7H), 5.49 (s, 1H), 5.02
(s, 1H), 4.53 (s, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 2.47 (bs, 1H), 2.05
F
dx.doi.org/10.1021/jo501658s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
54.7, 54.3, 53.5, 52.6, 52.4, 43.6, 40.5, 26.9, 26.8, 26.7, 19.4, 19.4, 18.6,
17.1, 14.4, 14.4; IR (ATR, cm−1) 3402, 2955, 2929, 2856, 1732, 1427,
1223, 1110, 700; HRMS (ESI+) calcd for C32H40NO3Si [M + H]+
514.2772, found 514.2778.
Pd(OAc)2, and 4.0 mL of AcOH. Rf (hexane/AcOEt 4:1) = 0.37; H
NMR (400 MHz, CDCl3) δ 7.51−7.46 (m, 2H), 7.40−7.17 (m, 6H),
6.82 (d, 1H, J = 7.3 Hz), 5.94 (t, 1H, J = 2.5 Hz), 4.30 (dd, 1H, J =
20.5, 2.5 Hz), 4.23 (dd, 1H, J = 20.5, 2.4 Hz), 4.17 (q, 2H, J = 7.2 Hz),
3.69 (s, 3H), 3.69 (d, 1H, J = 13.9 Hz), 3.11 (d, 1H, J = 13.9 Hz), 1.29
(t, 3H, J = 7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 174.4, 166.3,
165.2, 141.1, 140.4, 135.1, 129.4, 129.1, 128.5, 127.8, 127.7, 127.7,
126.6, 116.8, 67.8, 60.1, 52.8, 46.0, 41.6, 14.5; IR (ATR, cm−1) 3402,
2978, 1723, 1699, 1609, 1447, 1369, 1218, 1202, 730; HRMS (ESI+)
calcd for C22H24NO4 [M + H]+ 366.1700, found 366.1705.
(Z)-Methyl 4-(Cyanomethylene)-1-propyl-1,2,3,4-tetrahydroiso-
quinoline-1-carboxylate (6f). Compound 6f was obtained in 68%
yield (0.088 g) as a yellow oil from 0.103 g of amine 5a, 0.038 g of
allene 1f, 0.061 g of benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL
of AcOH. Rf (hexane/AcOEt 4:1) = 0.26; 1H NMR (400 MHz,
CDCl3) δ 7.55 (m, 2H), 7.46−7.40 (m, 1H), 7.34−7.28 (m, 1H), 5.73
(t, 1H, J = 1.2 Hz), 4.05 (d, 2H, J = 1.3 Hz), 3.75 (s, 3H), 2.30 (bs,
1H), 2.09 (m, 1H), 1.95 (ddd, 1H, J = 14.0, 9.7, 6.9 Hz), 1.38−1.23
(m, 2H), 0.91 (t, 3H, J = 7.4 Hz); 13C NMR (101 MHz, CDCl3) δ
174.0, 154.9, 138.2, 131.2, 130.2, 127.8, 127.8, 124.4, 117.1, 89.8, 65.1,
52.9, 44.7, 41.9, 17.6, 14.3; IR (ATR, cm−1) 3402, 2958, 2872, 2211,
1727, 1448, 1220, 730; HRMS (ESI+) calcd for C16H19N2O2 [M +
H]+ 271.1441, found 271.1446.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(Z)-Ethyl 2-(1,1-Dimethyl-2,3-dihydroisoquinolin-4(1H)-ylidene)-
acetate (8b). Compound 8b was obtained in 31% yield (0.053 g)
as a brown oil from 0.094 g of amine 5b, 0.094 g of allene 1a, 0.084 g
of benzoquinone, 0.008 g of Pd(OAc)2, and 5.0 mL of AcOH. Rf
AUTHOR INFORMATION
Corresponding Authors
*E-mail: xariza@ub.edu.
*E-mail: jordigarciagomez@ub.edu.
■
1
(hexane/AcOEt 3:2) = 0.20; H NMR (400 MHz, CDCl3) δ 7.55 (d,
1H, J = 7.9 Hz), 7.33−7.12 (m, 3H), 6.22 (t, 1H, J = 1.7 Hz), 4.33 (d,
2H, J = 1.8 Hz), 4.14 (q, 2H, J = 7.1 Hz), 1.39 (s, 6H), 1.25 (t, 3H, J =
7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 166.8, 152.2, 147.0, 131.4,
130.1, 126.7, 125.2, 125.0, 111.3, 60.1, 52.7, 42.6, 29.2, 14.5; HRMS
(ESI+) calcd for C15H20NO2 [M + H]+ 246.1489, found 246.1492.
(Z)-Ethyl 2-(1,1-Diethyl-2,3-dihydroisoquinolin-4(1H)-ylidene)-
acetate (8c). Compound 8c was obtained in less than 18% yield
(impure) as a brown oil from 0.092 g of amine 5c, 0.080 g of allene 1a,
0.068 g of benzoquinone, 0.006 g of Pd(OAc)2, and 4.0 mL of AcOH.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors thank the Ministerio de Educacion
Spain (CTQ2009-9692 and CTQ2009-11501) and CIBERobn
for financial support. We thank the University of Barcelona for
a fellowship to A.R.
■
́
y Ciencia of
1
Rf (hexane/AcOEt 7:3) = 0.21; H NMR (400 MHz, CDCl3) δ 7.65
(dd, 1H, J = 7.9, 1.0 Hz), 7.34 (td, 1H, J = 7.6, 1.3 Hz), 7.26−7.16 (m,
2H), 6.28 (t, 1H, J = 1.9 Hz), 4.38 (d, 1H, J = 1.9 Hz), 4.21 (q, 2H, J =
7.1 Hz), 1.87 (dq, 2H, J = 14.9, 7.5 Hz), 1.72 (dq, 2H, J = 14.6, 7.4
Hz), 1.32 (t, 3H, J = 7.1 Hz), 0.82 (t, 6H, J = 7.4 Hz); 13C NMR (101
MHz, CDCl3) δ 166.8, 152.5, 144.7, 132.8, 129.7, 126.6, 125.8, 125.5,
111.2, 60.1, 57.8, 42.5, 30.9, 14.5, 8.3; HRMS (ESI+) calcd for
C17H24NO2 [M + H]+ 274.1802, found 274.1799.
(Z)-Methyl 4-(2-Ethoxy-2-oxoethylidene)-1-methyl-1,2,3,4-tetra-
hydroisoquinoline-1-carboxylate (8d). Compound 8d was obtained
in 52% yield (0.074 g) as a colorless oil from 0.100 g of amine 5d,
0.055 g of allene 1a, 0.048 g of benzoquinone, 0.005 g of Pd(OAc)2,
and 4.0 mL of AcOH. Rf (hexane/AcOEt 7:3) = 0.15; 1H NMR (400
MHz, CDCl3) δ 7.67 (d, 1H, J = 7.8 Hz), 7.42−7.34 (m, 2H), 7.33−
7.27 (m, 1H), 6.35 (t, 1H, J = 1.7 Hz), 4.53 (dd, 1H, J = 17.6, 1.6 Hz),
4.31 (dd, 1H, J = 17.6, 2.0 Hz), 4.21 (q, 2H, J = 7.1 Hz), 3.73 (s, 3H),
2.56 (bs, 1H), 1.71 (s, 3H), 1.32 (t, 3H, J = 7.1 Hz); 13C NMR (101
MHz, CDCl3) δ 174.6, 166.6, 150.3, 139.9, 131.6, 130.1, 127.8, 126.6,
124.9, 111.9, 61.4, 60.2, 52.8, 43.0, 26.6, 14.4.
Methyl 1-Benzyl-4-(2-ethoxy-2-oxoethylidene)-1,2,3,4-tetrahy-
droisoquinoline-1-carboxylate (8h). Compound 8h was obtained as
a 87:13 Z:E mixture of stereoisomers in 58% yield (0.083 g) as a
colorless solid from 0.100 g of amine 5h, 0.055 g of allene 1a, 0.048 g
of benzoquinone, 0.005 g of Pd(OAc)2, and 4.0 mL of AcOH. Rf
(hexane/AcOEt 4:1) = 0.30; 1H NMR (400 MHz, CDCl3) δ 7.78 (m,
1H), 7.69−7.65 (m, 1H), 7.47−7.41 (m, 1H), 7.34−7.29 (m, 1H),
7.27−7.22 (m, 3H), 7.17−7.13 (m, 2H), 6.34 (m, 0.15H), 6.31 (m,
0.85H), 4.55 (dd, 0.85H, J = 16.7, 1.3 Hz), 4.45 (dd, 0.15H, J = 20.6,
2.3 Hz), 4.24−4.15 (m, 3H), 3.69 (s, 2.55H), 3.65 (s, 0.45H), 3.64 (d,
1H, J = 13.5 Hz), 3.17 (d, 1H, J = 13.5 Hz), 2.29 (bs, 1H), 1.30 (t, 3H,
J = 7.1 Hz); 13C NMR (101 MHz, CDCl3) δ 173.7, 166.6, 150.3,
138.3, 135.7, 132.6, 130.5, 130.1, 128.4, 127.8, 127.8, 127.3, 125.0,
111.7, 64.9, 60.2, 52.6, 46.0, 42.3, 14.5; IR (ATR, cm−1) 3402, 2979,
1703, 1619, 1370, 1158, 730; HRMS (ESI+) calcd for C22H24NO4 [M
+ H]+ 366.1700, found 366.1704.
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G
dx.doi.org/10.1021/jo501658s | J. Org. Chem. XXXX, XXX, XXX−XXX

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