Construction of mononitrogen heterocycles with a combined system of 1-azaspiro[4.n]alkene and 3-benzazocine fragments through the intramolecular eight-membered Heck cyclization

Article abstract of DOI:10.1007/s11172-010-0252-7

Amides, obtained from 1-azaspiro[4.n]alkenes (n = 3, 4, 5) and 2-(6-bromo-1,3-benzo-dioxol-5-yl)acetyl chloride, upon heating with a Herrmann-Beller palladium catalyst undergo intramolecular cyclization by the Heck reaction to form pentacyclic compounds (up to 94% yield) including an 1-azaspiro[4.n]alkene (n = 4, 5) fragment and a new eight-membered 3-benzazocine ring. The structure of the thus obtained pentacycles with the 1-azaspiro[4.4]non-7-ene fragment is isomeric to the structure of the main core of alkaloid cephalotaxine. In the case of 1-azaspiro[4.5]dec-2-ene derivative, the reaction is accompanied by the reduction of bromo amide, with the yield of the cyclization product being 34%. The starting 1-azaspiro-[4.n]alkenes (n = 3, 4, 5) were synthesized by the reductive diallylboration of 3-chloropropion- itrile or the corresponding lactams (piperidin-2-one, (2S)-2-hydroxymethyl-and 5,5-di-methylpyrrolidin-2-one) with subsequent intramolecular metathesis upon the action of Grubbs catalyst.

Full text of DOI:10.1007/s11172-010-0252-7

Russian Chemical Bulletin, International Edition, Vol. 59, No. 7, pp. 1393—1399, July, 2010
1393
Construction of mononitrogen heterocycles with a combined system
of 1ꢀazaspiro[4.n]alkene and 3ꢀbenzazocine fragments
through the intramolecular eightꢀmembered Heck cyclization
N. Yu. Kuznetsov, V. N. Khrustalev, and Yu. N. Bubnov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: nkuznff@ineos.ac.ru
Amides, obtained from 1ꢀazaspiro[4.n]alkenes (n = 3, 4, 5) and 2ꢀ(6ꢀbromoꢀ1,3ꢀbenzoꢀ
dioxolꢀ5ꢀyl)acetyl chloride, upon heating with a Herrmann—Beller palladium catalyst undergo
intramolecular cyclization by the Heck reaction to form pentacyclic compounds (up to 94%
yield) including an 1ꢀazaspiro[4.n]alkene (n = 4, 5) fragment and a new eightꢀmembered
3ꢀbenzazocine ring. The structure of the thus obtained pentacycles with the 1ꢀazaspiro[4.4]nonꢀ
7ꢀene fragment is isomeric to the structure of the main core of alkaloid cephalotaxine. In the
case of 1ꢀazaspiro[4.5]decꢀ2ꢀene derivative, the reaction is accompanied by the reduction of
bromo amide, with the yield of the cyclization product being 34%. The starting 1ꢀazaspiroꢀ
[4.n]alkenes (n = 3, 4, 5) were synthesized by the reductive diallylboration of 3ꢀchloropropionꢀ
itrile or the corresponding lactams (piperidinꢀ2ꢀone, (2S)ꢀ2ꢀhydroxymethylꢀ and 5,5ꢀdiꢀ
methylpyrrolidinꢀ2ꢀone) with subsequent intramolecular metathesis upon the action of
Grubbs catalyst.
Key words: 3ꢀbenzazocine, allylboration, metathesis, the Heck reaction, palladacycle, Cephꢀ
alotaxine, spiro compounds, mediumꢀsized rings.
Sevenꢀ and eightꢀmembered azaheterocycles are the
structural fragments of many alkaloids and biologically
active compounds possessing pharmacologically useful
properties.1—3 At the same time, it is known for a long
time that the use of cyclization reactions and other tradiꢀ
tional methods of organic chemistry for the construction
of mediumꢀsized (sevenꢀ and eightꢀmembered) rings is
inefficient due to the unfavorable enthalpy and entropy
factors.4 At the same time, metal complex catalysis5 and
especially metathesis reactions of dienes with terminal
multiple bonds and the Heck cyclization reaction6 allows
one to obtain a wide variety of compounds of this type.
Alkaloid cephalotaxine (CPT) is one of the natural
compounds containing 3ꢀbenzazepine (sevenꢀmembered)
ring, it is produced by yewꢀtrees growing in China and
Japan (Cephalotaxus harrigtonia and fortunei var. Drupaꢀ
cea). Esters of CPT (harringtonines) possess high antileuꢀ
cemia (myeloid leukemia, clinical trials)7a,b and antimaꢀ
laria activity.7c Therefore, preparation of both CPT and its
structural analogs is an actual problem. The presence of a
spiroꢀjoint system bound to the benzazepine ring is anothꢀ
er characteristic feature of a CPT molecule. To form the
B, C, and D system of rings of a CPT molecule, two
palladium catalyzed cyclizations (allylic amination and
the Heck reaction) were successfully used7d (Scheme 1).
The same methodology were applied7e,f for obtaining
a number of close structural analogs of CPT with B, C,
and D rings of various sizes. Attempts to use this approach
for the synthesis of the eightꢀmembered ring B were unꢀ
successful.
Scheme 1
i. 4 mol.% [Pd], Bu4NOAc, MeCN/DMF/H2O, 110—120 °C, 10 h;
[Pd] =
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1363—1369, July, 2010.
1066ꢀ5285/10/5907ꢀ1393 © 2010 Springer Science+Business Media, Inc.

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Kuznetsov et al.
Scheme 3
During accomplishing our program on the use of allylꢀ
ic boranes in the synthesis of heterocyclic compounds,8
we have developed an efficient method for obtaining
1ꢀazaspiro[4.n]alkenes based on the diallylboration of lacꢀ
tams with subsequent intramolecular metathesis (RCM)
of diallylated products.8c This method was used for the
synthesis of spiranes with fiveꢀ, sixꢀ, sevenꢀ, and 13ꢀmemꢀ
bered azacycles, that henceforth allowed us to develop
a formal total synthesis of ( )ꢀcephalotaxine.9 Our first
attempt to use the Heck reaction for the construction of
the azepine ring B of the cephalotaxine core led to a disꢀ
covery of a new cyclization, whose product was a structurꢀ
al isomer of the CPT core with the 3ꢀbenzazocine eightꢀ
membered ring B (Scheme 2).10
i. HCl, dioxane.
Cy is cyclohexyl
Scheme 2
Comꢀ
pound
3a
3b
3c
R1
R2
n
Yield
(%)
99
83
97
,
CH2OH
Me
H
Me
H
1
1
2
H
Scheme 4
Reagents and conditions: 5 mol.% [Pd], MeCN—DMF—H2O,
NaOAc, 140 °C, 13 h.
Developing this area, we have synthesized a series of
1ꢀazaspiro[4.n]alkenes and accomplished their cyclization
upon the action of a palladium catalyst (by the Heck reacꢀ
tion). This resulted in obtaining new 3ꢀbenzazocine derivꢀ
atives with fiveꢀ and sixꢀmembered azacycle C and differꢀ
ent substituents in the spiro fragment, that indicates
a general character of the cyclization.
Starting from (2S)ꢀ2ꢀhydroxymethylpyrrolidinꢀ, 5,5ꢀdiꢀ
methylpyrrolidinꢀ, piperidinꢀ2ꢀone and 3ꢀchloropropionꢀ
itrile, derivatives of 1ꢀazaspiro[4.n]alkenes with fourꢀ, fiveꢀ,
and sixꢀmembered azacycle (3a—c)9 were obtained
(Schemes 3 and 4).
The reaction of lactams containing an N—H bond with
triallylborane leads to diallylated heterocycles 1. The latꢀ
ter were further transformed to NꢀBocꢀderivatives 2 with
subsequent intramolecular cyclization (RCM) in the presꢀ
ence of a Grubbs catalyst [Ru]. Removal of the protecting
group in 2 was carried out upon the action of HCl in
dioxane, that gave the corresponding hydrochlorides 3 in
83—99% yield. Azetidine derivative 2 (R1 = R2 = H, n = 0)
was an exception, which decomposed upon the action of
strong acids. Hydrochlorides 3a—c were acylated with
2ꢀ(6ꢀbromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)acetyl chloride 4 by the
i. 1 mol.% [Ru], CH2Cl2.
Comꢀ
pound
5a
R1
R2
n
Yield
(%)
96
83
94
91
CH2OH
H
Me
H
1
1
2
0
5b
5c
Me
H
5d
H
H

8ꢀMembered Heck cyclization of azaspiroalkenes
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1395
Scheme 5
i. 5 mol.% [Pd], DMF/MeCN/H2O, 125 °C, 5 h. 82% total yield.
Schotten—Baumann reaction (20% aq. NaOH, CH2Cl2)
(Scheme 4), and the amides 5a—c formed were isolated in
83—96% yield by crystallization or chromatography.
Amide 5d was synthesized by acylation of 2,2ꢀdiallylazetiꢀ
dine and subsequent metathesis reaction (see Scheme 4).
The amides 5a—d obtained underwent cyclization by
the Heck reaction10 in the presence of the Hermann—Belꢀ
ler palladacycle [Pd] in catalytic amount (its structure is
given in Scheme 1). Cyclization of chiral amide 5a with
2ꢀhydroxymethyl substituent leads to diastereomeric alꢀ
cohols 6a and 7a (Scheme 5) in the ratio 1.6 : 1 (according
C(14), and C(17) atoms with known (S)ꢀconfiguration at
the C(14) atom, and it crystallizes in the P212121 chiral
space group. Thus, the asymmetric centers have the
(1R,14S,17S) absolute configuration. In crystal, the molꢀ
ecules are bound through the intermolecular hydrogen
bonds O—H...O (O(1)—H(10)...O(12) (x + 1/2, –y + 3/2,
–z + 1), O...O 2.820(1), H...O 2.05 Å, O—H...O 158°).
The bond distances and angles in the molecule have stanꢀ
dard values.
2,2ꢀDimethylꢀsubstituted amide 5b also readily gives
cyclization product 6b (Scheme 6), which after chromatoꢀ
1
to the H NMR spectra of the reaction mixture), that
indicates an insignificant effect of the substituent on the
diastereoselectivity of the process. The cyclization of 5a
reaches completion within 5 h at 125 °C, whereas the cycliꢀ
zation of unsubstituted amide (see Scheme 2) requires more
drastic conditions (140 °C, 13 h).10 This effect can be exꢀ
plained by the formation of hydrogen bonds between the
oxygen atom of the carboxamide group and the hydroxy
group, that leads to some stabilization of such conformaꢀ
tion of molecule 5a, which is favorable for the cyclization.
The structure of the major isomer of 6a was established
by Xꢀray diffraction (Fig. 1). The eightꢀmembered ring
in compound 6a has the chair conformation with the plaꢀ
nar central fragment C(1)—C(20)/C(11)—C(12). This
compound has three asymmetric centers at the C(1),
Scheme 6
C(19)
C(17) C(18)
C(1)
C(2)
C(3)
C(20)
C(16)
C(15)
O(5)
C(4)
O(7)
C(9)
C(10)
C(12)
C(6)
C(8)
C(21)
O(1)
C(11)
O(12)
C(14)
N(13)
Fig. 1. Molecular structure of 6a is represented by ellipsoids of
thermal vibrations with 50% probability.
Reagents and conditions: 5 mol.% [Pd], DMF—MeCN—H2O,
125 °C; 10 h (i); 16 h (ii).

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Kuznetsov et al.
94 (40); 93 (23); 92 (100); 91 (96); 80 (50); 79 (46); 77 (59);
51 (16); 41 (33); 39 (36). Found (%): C, 56.98; H, 8.61; N, 7.41.
C9H16NOCl (189.7). Calculated (%): C, 56.99; H, 8.50; N, 7.38.
2,2ꢀDimethylꢀ1ꢀazaspiro[4.4]nonꢀ7ꢀene hydrochloride (3b).
NꢀВocꢀProtected 2,2ꢀdimethylꢀ1ꢀazaspiro[4.4]nonꢀ7ꢀene9 (1.03 g,
4.1 mmol) was treated with a solution of HCl in dioxane (5.06 M,
2 mL, 10.2 mmol) at 70 °C for 30 min as in the case of 3a to
obtain 3b (0.64 g, 83%) as brown crystals, m.p. >260 °C (with
decomp.). 1H NMR (300 MHz, CDCl3), δ: 9.53 (br.s, 2 H,
NH2+); 5.61 (s, 2 H, CH=); 3.35 (d, 2 H, CH2CH=, J = 15.5 Hz);
2.47 (d, 2 H, CH2CH=, J = 15.5 Hz); 2.07 (t, 2 H, CH2,
J = 7.3 Hz); 1.87 (t, 2 H, CH2C, J = 7.3 Hz); 1.56 (s, 6 H, 2Me).
13C NMR (75 MHz, CDCl3), δ: 128.39; 72.83; 65.07; 44.60;
38.23; 37.97; 27.26. MS (70 eV, EI): m/z 151 [M+ – HCl] (32);
137 (10); 136 [M+ – HCl – CH3] (100); 119 (20); 108 (12);
95 (23); 94 (89); 91 (26); 82 (40); 80 (22); 79 (21); 77 (24);
67 (16); 51 (10); 49 (30). Found (%): C, 63.94; H, 9.72; N, 7.69.
C10H18NCl (187.7). Calculated (%): C, 63.99; H, 9.67; N, 7.46.
6ꢀAzaspiro[4.5]decꢀ2ꢀene hydrochloride (3c). NꢀВocꢀProꢀ
tected 6ꢀazaspiro[4.5]decꢀ2ꢀene8 (1.07 g, 4.5 mmol) was treated
with a solution of HCl in dioxane (5.37 M, 1.87 mL, 10.0 mmol)
at 70 °C for 30 min as in the case of 3a to obtain 3c (0.72 g, 97%)
as beige crystals, m.p. 185—186 °C. 1H NMR (300 MHz,
CDCl3), δ: 9.55 (br.s, 2 H, NH2+); 5.61 (s, 2 H, CH=); 3.06
(br.s, 2 H, CH2N); 2.85 (d, 2 H, CH2CH=, J = 15.9 Hz); 2.47
(d, 2 H, CH2CH=, J = 15.8 Hz); 1.83 (br.s, 4 H, 2CH2);
1.62—1.61 (m, 2 H, CH2C). 13C NMR (75 MHz, CDCl3), δ:
127.72; 64.16; 42.54; 41.79; 33.83; 21.63; 19.51. MS (70 eV, EI):
m/z 137 [M+ – HCl] (45); 136 (72); 134 (12); 123 (12); 122 (96);
110 (17); 109 (19); 108 (59); 96 (20); 95 (54); 94 (100); 93 (30);
91 (33); 82 (27); 80 (72); 79 (23); 77 (30); 67 (21); 54 (17);
39 (12). Found (%): C, 62.21; H, 9.32; N, 7.99. C9H16NCl
(173.7). Calculated (%): C, 62.24; H, 9.29; N, 8.06.
graphic purification was isolated in crystalline form in
94% yield.
Unsubstituted amide 5c with the sixꢀmembered (pipeꢀ
ridine) ring in the spiro fragment undergoes the cyclizaꢀ
tion much less efficiently: together with pentacyclic prodꢀ
uct 6c (34%), a reduced amide 8 was obtained in 15%
yield (see Scheme 6). Our attempts to carry out the cyꢀ
clization of amide 5d containing a fourꢀmembered ring
(azetidine derivative) were unsuccessful: in all the cases,
an unseparable mixture of compounds, apparently, deꢀ
composition products, was obtained.
In conclusion, we discovered a new type of cyclization
by the Heck reaction. Amides 5a—c upon heating (125 °C)
in the presence of the Hermann—Beller7g palladacycle
[Pd] (see Scheme 1) undergo the eightꢀmembered cyclizaꢀ
tion to form pentacyclic compounds 6a—c and 7a conꢀ
taining a 3ꢀbenzazocine fragment. The cyclization is
the most efficient (80—94%) for amides 5a,b including
a 1ꢀazaspiro[4.4]nonꢀ7ꢀene system; the structure of the
pentacycles obtained is isomeric to the structure of the
main core of alkaloid cephalotaxine. Note that chiral
amide 5a containing a hydroxymethyl group is a prospecꢀ
tive model substrate for the study of activity of chiral cataꢀ
lysts of the Heck reaction.
Experimental
2,2ꢀDiallylazetidine and the corresponding NꢀВocꢀprotectꢀ
ed spiranes 2 were obtained according to the procedures deꢀ
scribed earlier.8,9 NMR spectra were recorded on a Bruker
AMХꢀ400 and Bruker Avanceꢀ300 spectrometers. Mass spectra
were recorded on a Finnigan Polaris Q Ion Trap instrument.
Column chromatography was performed using 60—230 mesh
silica gel (Merck). Elemental analysis was performed on a Carꢀ
loꢀErba 1106 automatic analyser. Grubbs catalyst [Ru] was purꢀ
chased from Aldrich. Hermann—Beller palladacycle [Pd] was
prepared from palladium acetate and triꢀoꢀtolylphosphine acꢀ
cording to the known procedure.7g
{(2S)ꢀ1ꢀ[(6ꢀBromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)acetyl]ꢀ1ꢀazaspiroꢀ
[4.4]nonꢀ7ꢀenꢀ2ꢀyl}methanol (5a). Acyl chloride 4 (0.34 g,
1.23 mmol) was added to a solution of 3a (0.22 g, 1.16 mmol) in
CH2Cl2 (5 mL) at 0 °C, followed by immediate addition of 20%
aqueous NaOH (1.0 mL, 6.2 mmol) with vigorous stirring. The
reaction progress was monitored by TLC (nꢀhexane : EtOAc =
= 1 : 2, Rf (5a) = 0.4). Powdered K2CO3 (3 g) was added to the
reaction mixture, a suspension obtained was filtered, washed
with CH2Cl2. The filtrate was concentrated at reduced presꢀ
sure, a residual oil was subjected to chromatography in the
nꢀhexane : EtOAc = 1 : 2 system to obtain 5a (0.44 g, 96%) as an
(2S)ꢀ1ꢀAzaspiro[4.4]nonꢀ7ꢀenꢀ2ꢀylmethanol hydrochloride
(3a). A solution of HCl in dioxane (5.06 M, 1.26 mL, 6.4 mmol)
was added to a solution of NꢀВocꢀprotected (2S)ꢀ1ꢀazaspiroꢀ
[4.4]nonꢀ7ꢀenꢀ2ꢀylmethanol9 (0.65 g, 2.56 mmol) in dioxane
(2 mL), the mixture obtained was heated at 70 °C for 40 min
(TLC monitoring, nꢀhexane : EtOAc = 1 : 1). After the reaction
reached completion, the mixture was diluted with Et2O (5 mL)
and left to crystallize, a precipitate formed was filtered off and
dried in vacuo to obtain 3a (0.48 g, 99%) as white crystals,
25
oil, [α]D –6.0 (c = 1; CHCl3). Due to the hindered rotation in
the amide group, doubling, overlap, and broadening of some signals
1
are observed in the NMR spectra. H NMR (300 MHz, CDCl3),
δ: 6.96 and 6.94 (both s, total 1 H, (HC=)arom); 6.75 and 6.71
(both s, total 1 H, (HC=)arom); 5.92 and 5.90 (both s, total 2 H,
OCH2O); 5.72 and 5.61—5.55 (s and m, total 2 H, CH=);
4.45—4.41 (m, 0.73 H); 4.07—4.04 (m, 0.69 H); 3.80 and 3.75
(both s, total 0.68 H); 3.71—3.62 (m, 1.29 H); 3.60 and 3.56
(both s, total 0.75 H); 3.55—3.54 (m, 0.59 H); 3.48—3.39
(m, 0.71 H); 3.35 (d, 0.66 H, J = 16.2 Hz); 3.15—2.84 (m, 2 H);
2.64—2.51 (m, 0.76 H); 2.10—1.89 (m, 5 H); 1.72—1.67 (m, 0.4 H).
13C NMR (100 MHz, C6D6), δ: 172.52; 168.78; 147.36; 147.31;
147.28; 129.26; 129.18; 128.87; 128.77; 128.39; 128.23; 115.19;
115.07; 112.64; 112.47; 111.34; 110.87; 101.78; 101.68; 70.61;
68.91; 67.14; 63.58; 63.24; 60.88; 48.67; 47.63; 44.78; 44.37;
44.11; 42.50; 41.03; 40.99; 25.71; 25.61. MS (70 eV, EI): m/z
395/393 [M+] (9); 327 (37); 314 (94); 271 (50); 269/267 (15);
1
m.p. 112.5—113.5 °C, [α]D25 +12.8 (c = 1; MeOH). H NMR
(400 MHz, DMSOꢀd6), δ: 9.80 (br.s, 1 H, NH2+); 9.06 (br.s,
1 H, NH2+); 5.74—5.70 (m, 2 H, CH=); 5.43 (br.s, 1 H, OH);
3.76—3.60 (m, 3 H, CH2OH and CHNH2+); 2.99 (d, 1 H,
CH2CH=, J = 17.4 Hz); 2.84 (d, 1 H, CH2CH=, J = 17.2 Hz);
2.48 (dm, 2 H, CH2CH=, J = 16.1 Hz); 2.07 (dddd, 1 H,
CHaHbCHN, J = 5.7 Hz, J = 7.1 Hz, J = 8.3 Hz, J = 16.3 Hz);
1.96 (m, 2 H, CH2C); 1.86—1.77 (m, 1 H CHaHbCHN).
13C NMR (100 MHz, DMSOꢀd6), δ: 133.65; 133.36; 77.09;
65.21; 65.31; 47.26; 47.07; 41.65; 29.88. MS (70 eV, EI): m/z 154
[M+ – Cl] (2); 153 [M+ – HCl] (8); 122 (30); 108 (21); 105 (20);

8ꢀMembered Heck cyclization of azaspiroalkenes
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1397
254 (64); 247 (46); 215 (56); 213 (36); 210 (41); 204 (32); 189 (43);
169 (25); 166 (22); 149 (69); 141/139 (10); 136/134 (12); 133 (26);
123 (25); 122 (100); 121 (20); 119 (36); 105 (51); 99 (20); 97 (31);
95 (35); 93 (32); 91 (42); 85 (49); 81/79 (43); 71 (50); 67 (43);
57 (75); 55 (36). Found (%): C, 56.14; H, 7.09; N, 4.00; Br, 23.28.
C18H20NO4Br (394.3). Calculated (%): C, 54.84; H, 5.11;
N, 3.55; Br, 20.27.
cycles of freezing—evacuation—filling with argon. The degassed
mixture was capped and heated at 125 °C for the time indicated
in the corresponding Scheme. After the reaction reached comꢀ
pletion, the mixture was filtered and concentrated at reduced
pressure, the residue was diluted with water (30 mL) and extractꢀ
ed with EtOAc (3×8 mL). Combined extracts were dried with
K2CO3 and concentrated at reduced pressure. The residue was
purified by column chromatography, eluting with EtOAc to isoꢀ
late isomers 6a and 7a in overall 82% yield.
1ꢀ[(6ꢀBromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)acetyl]ꢀ2,2ꢀdimethylꢀ1ꢀ
azaspiro[4.4]nonꢀ7ꢀene (5b). Compound 5b was obtained simiꢀ
larly to 5a, from 3b (0.38 g, 2.0 mmol) and acyl chloride 4 (0.64 g,
2.3 mmol) in CH2Cl2 (8 mL) upon alkalination with 20%
aq. NaOH (0.8 mL, 5.0 mmol). After workꢀup and concentraꢀ
tion, a residual oil was heated with hexane for crystallization to
obtain 5b (0.70 g, 90%) as a white powder, m.p. 130—131 °C.
Due to the hindered rotation in the amide group, doubling, overlap,
and broadening of some signals are observed in the NMR spectra.
1H NMR (300 MHz, CDCl3), δ: 6.96 (s, 1 H, (HC=)arom); 6.78
and 6.75 (both s, total 1 H, (HC=)arom); 5.91 (s, 2 H, OCH2O);
5.70 and 5.59 (both s, total 2 H, CH=); 3.68 and 3.45 (both s,
total 2 H, CH2C=O); 3.14 and 2.95 (both d, total 2 H, CH2CH=,
J = 14.2 Hz and 15.3 Hz); 2.56 and 2.09 (both d, total 2 H,
CH2CH=, J = 15.3 Hz and 14.2 Hz); 1.99 (t, 1 H, CHaHb,
J = 7.1 Hz); 1.92—1.82 (m, 2 H, CH2); 1.76 (t, 1 H, CHaHb,
J = 7.1 Hz); 1.54 and 1.49 (both s, total 6 H, 2 CH3). 13C NMR
(75 MHz, CDCl3), δ: 169.32; 168.52; 147.22; 147.17; 147.13;
146.99; 129.57; 129.53; 129.09; 128.64; 115.11; 112.59; 111.72;
111.14; 101.61; 72.93; 69.21; 65.08; 61.46; 48.77; 45.02; 43.48;
42.85; 42.53; 41.37; 39.93; 39.10; 28.74; 26.54. MS (70 eV, EI):
m/z 312 [M+ – Br] (100); 260/258 (3); 242/240 (3); 215/213
(14); 179 (12); 178 (65); 136 (11); 107 (7); 91 (9); 77 (11).
Found (%): C, 58.21; H, 5.69; N, 3.62; Br, 20.19. C19H22NO3Br
(392.3). Calculated (%): C, 58.17; H, 5.65; N, 3.57; Br, 20.37.
[(6ꢀBromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)ꢀacetyl]ꢀ6ꢀazaspiro[4.5]ꢀ
decꢀ2ꢀene (5c). Compound 5c was obtained similarly to 5a, from
3c (0.50 g, 2.87 mmol) and acyl chloride 4 (1.10 g, 4.0 mmol) in
CH2Cl2 (8 mL) upon alkalination with 20% aq. NaOH (2.6 mL,
16.0 mmol). After workꢀup and concentration, a residual oil was
heated with hexane for crystallization to obtain 5c (1.02 g, 94%)
as a cream powder, m.p. 111—112 °C. 1H NMR (300 MHz,
CDCl3), δ: 6.97 (s, 1 H, (HC=)arom); 6.77 (s, 1 H, (HC=)arom);
5.92 (s, 2 H, OCH2O); 5.60 (s, 2 H, 2 CH=); 3.67 (s, 2 H,
CH2C=O); 3.45—3.42 (m, 2 H, CH2N); 2.93 (d, 2 H, CH2CH=,
J = 14.6 Hz); 2.36 (d, 2 H, CH2CH=, J = 14.6 Hz); 1.67—1.60
(m, 6 H, 3 CH2). 13C NMR (75 MHz, CDCl3), δ: 170.27; 147.36;
147.23; 128.82; 128.33 (2 C); 114.95; 112.54; 110.65; 101.67;
65.31; 44.03(2C); 43.49; 42.80; 34.43; 23.87; 17.41. MS (70 eV,
EI): m/z 379/377 [M+] (0.5); 299 (23); 298 [M+ – Br] (100);
215 (14); 213 (13); 178 (15); 164 (12); 136 (10); 135 (10); 91 (18);
77 (11). Found (%): C, 57.12; H, 5.29; N, 3.76; Br, 21.27.
C18H20NO3Br (378.3). Calculated (%): C, 57.15; H, 5.33;
N, 3.70; Br, 21.12.
Compound 6a. The yield was 0.152 g (48.5%), clear crystals,
Rf = 0.23 (EtOAc); m.p. 204—205 °C, [α]D +134.4 (c = 1;
25
CHCl3). 1H NMR (400 MHz, CDCl3), δ: 6.71 (s, 1 H, (HC=)arom);
6.60 (s, 1 H, (HC=)arom); 6.05 (dd, 1 H, CH=, J = 2.9 Hz,
J = 5.3 Hz); 5.88 (d, 1 H, OCHaHbO, J = 1.4 Hz); 5.85 (d, 1 H,
OCHaHbO, J = 1.4 Hz); 5.82 (d, 1 H, CH=, J = 5.3 Hz); 4.92
(d, 1 H, CHaHbC=O, J = 13.1 Hz); 4.40 (ddd, 1 H, CHN,
J = 5.7 Hz, J = 7.5 Hz, J = 6.9 Hz); 4.00 (t, 1 H, OH, J = 4.8 Hz);
3.80 (dd, 1 H, CHAr, J = 1.7 Hz, J = 8.8 Hz); 3.66 (ddd, 1 H,
CHaHbOH, J = 3.5 Hz, J = 6.6 Hz, J = 10.6 Hz); 3.56 (dt, 1 H,
CHaHbOH, J = 5.2 Hz, J = 10.7 Hz); 3.12 (d, 1 H, CHaHbC=O,
J = 13.1 Hz); 2.33 (ddd, 1 H, CHaHbCHN, J = 6.8 Hz, 12.6 Hz,
13.5 Hz); 2.27 (dd, 1 H, CHaHbCHAr, J = 9.1 Hz, J = 13.4 Hz);
1.91 (dddd, 1 H, CHaHbCHN, J = 6.5 Hz, J = 9.1 Hz, J = 13.2 Hz,
J =15.3 Hz); 1.87 (d, 1 H, CHaHbCHAr, J = 13.6 Hz); 1.79—1.72
(m, 2 H, CH2C). 13C NMR (100 MHz, CDCl3), δ: 174.55;
146.74; 146.27; 135.22; 134.82; 134.51; 127.71; 113.97; 110.14;
101.10; 75.86; 66.60; 60.70; 53.01; 49.56; 40.52; 39.50; 24.63.
MS (70 eV, EI): m/z 313 [M+] (22); 283 (19); 282 (100); 255
(11); 254 (72); 237 (12); 212 (21); 211 (64); 210 (11); 199 (16);
181 (21); 172 (30); 153 (17); 115 (10); 82 (11). Found (%):
C, 69.07; H, 6.09; N, 4.48. C18H19NO4 (313.3). Calculated (%):
C, 68.99; H, 6.11; N, 4.47.
Compound 7a. The yield was 0.105 g (33.5%), oil, Rf = 0.31
25
1
(EtOAc); [α]D –184.8 (c = 1; CHCl3). H NMR (300 MHz,
CDCl3), δ: 6.71 (s, 1 H, (HC=)arom); 6.61 (s, 1 H, (HC=)arom);
6.08 (dd, 1 H, CH=, J = 3.0 Hz, J = 5.3 Hz); 5.90 (s, 1 H,
OCHaHbO); 5.88 (s, 1 H, OCHaHbO); 5.78 (d, 1 H, CH=,
J = 5.3 Hz); 5.04 (br.s, 1 H, OH); 5.01 (d, 1 H, CHaHbC=O,
J = 13.4 Hz); 4.37—4.29 (m, 1 H, CHN); 3.77 (dd, 1 H, CHAr,
J = 2.5 Hz, J = 8.7 Hz); 3.60—3.54 (m, 2 H, CH2OH); 3.14
(d, 1 H, CHaHbC=O, J = 13.2 Hz); 2.36 (dd, 1 H, CHaHbCHAr,
J = 8.9 Hz, J = 13.2 Hz); 2.23—2.13 (m, 1 H, CHaHbCHN);
2.07—1.98 (m, 2 H, CH2C); 1.94 (d, 1 H, CHaHbCHAr,
J = 13.2 Hz); 1.67—1.56 (m, 1 H, CHaHbCHN). 13C NMR
(75 MHz, CDCl3), δ: 173.91; 146.86; 146.28; 134.47; 134.33;
134.05; 127.39; 113.97; 110.23; 101.12; 74.50; 67.29; 64.31; 52.76;
50.04; 41.18; 38.89; 26.66. Found (%): C, 68.85; H, 5.97; N, 4.43.
C18H19NO4 (313.3). Calculated (%): C, 68.99; H, 6.11; N, 4.47.
(1S*,17R*)ꢀ14,14ꢀDimethylꢀ5,7ꢀdioxaꢀ13ꢀazapentacycloꢀ
[15.2.1.02,10.04,8.013,17]icosaꢀ2(10),3,8,18ꢀtetraenꢀ12ꢀone (6b).
The yield was 0.29 g (94%), m.p. 143—144 °C. Rf(5b) = 0.58
(nꢀhexane : EtOAc = 1 : 1). 1H NMR (300 MHz, CDCl3), δ:
6.71 (s, 1 H, (HC=)arom); 6.58 (s, 1 H, (HC=)arom); 5.97 (dd, 1 H,
CH=, J = 3.0 Hz, J = 5.5 Hz); 5.87 (d, 1 H, OCHaHbO,
J = 1.6 Hz); 5.85 (d, 1 H, OCHaHbO, J = 1.6 Hz); 5.78 (dd, 1 H,
CH=, J = 0.9 Hz, J = 5.5 Hz); 4.94 (d, 1H, CHaHbC=O,
J = 13.3 Hz); 3.73 (dd, 1 H, CHAr, J = 2.7 Hz, J = 8.9 Hz); 3.03
(d, 1 H, CHaHbC=O, J = 13.2 Hz); 2.31 (dd, 1 H, CHaHbCHAr,
J = 9.1 Hz, J = 13.5 Hz); 2.20 (dt, 1 H, CHaHbCHN, J = 8.0 Hz,
J = 12.6 Hz); 1.90—1.80 (m, 2 H, CHaHbCHN and CHaHbCHAr);
1.76—1.71 (m, 2 H, CH2C); 1.42 (s, 3 H, CH3); 1.40 (s, 3 H,
The Heck cyclization reaction. (1S,14S,17R)ꢀ14ꢀ(Hydroxymꢀ
ethyl)ꢀ5,7ꢀdioxaꢀ13ꢀazapentacyclo[15.2.1.02,10.04,8.013,17]icosaꢀ
2(10),3,8,18ꢀtetraenꢀ12ꢀone (6a) and (1R,14S,17S)ꢀ14ꢀ(hydrꢀ
oxymethyl)ꢀ5,7ꢀdioxaꢀ13ꢀazapentacyclo[15.2.1.02,10.04,8.013,17]ꢀ
icosaꢀ2(10),3,8,18ꢀtetraenꢀ12ꢀone (7a) (general procedure).
Amide 5a (0.39 g, 1.0 mmol), NaOAc (0.21 g, 2.6 mmol), [Pd]
catalyst (46 mg, 0.05 mmol, 5 mol.%), and nꢀBu4NBr (0.1 g,
0.31 mmol) were placed into a Schlenk vessel, followed by addiꢀ
tion of MeCN (5 mL), DMF (5 mL), and H2O (1 mL) to this
mixture of reagents. A suspension obtained was degassed by three

1398
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
Kuznetsov et al.
CH3). 13C NMR (75 MHz, CDCl3), δ: 171.45; 146.49; 146.09;
135.80; 134.45; 133.34; 128.50; 114.05; 109.94; 100.97; 75.33;
64.19; 52.94; 50.58; 43.03; 39.31; 38.12; 26.48; 26.25. MS (70 eV,
EI): m/z 311 [M+] (100); 296 (14); 268 (27); 253 (27); 255 (22);
213 (20); 212 (40); 211 (28); 199 (28); 195 (20); 181 (18); 172 (18);
153 (16); 115 (17); 49 (10). Found (%): C, 73.28; H, 6.90; N, 4.46.
C19H21NO3 (311.4). Calculated (%): C, 73.29; H, 6.80; N, 4.50.
to a degassed solution of 2,2ꢀdiallylꢀ1ꢀ[(6ꢀbromoꢀ1,3ꢀbenzodiꢀ
oxolꢀ5ꢀyl)acetyl]azetidine (1.30 g, 3.43 mmol) in CH2Cl2
(30 mL). The reaction mixture was heated for ~1.5 h at 37—40 °C,
monitoring the reaction progress by TLC, nꢀhexane : EtOAc =
= 4 : 1, Rf (5d) = 0.13. After the reaction reached completion,
the solvent was evaporated, the residue was dissolved in the
nꢀhexane : EtOAc = 4 : 1 mixture, and the solution obtained was
passed through the layer of silica gel (3.5×5 cm), then the prodꢀ
uct was eluted with the nꢀhexane : EtOAc = 3 : 1 mixture. The
solvents were evaporated to obtain compound 5d (1.09 g, 91%)
as an oil. Due to the hindered rotation in the amide group, douꢀ
bling, overlap, and broadening of some signals are observed in the
(1S*, 18R*)ꢀ5,7ꢀDioxaꢀ13ꢀazapentacyclo[16.2.1.02,10.04,8
13,18]heneicosaꢀ2(10),3,8,19ꢀtetraenꢀ12ꢀone (6c). The yield was
.
0
0.10 g (34%), white powder, m.p. 114.5—115.5 °C. Rf (5c) =
= 0.40 (nꢀhexane : EtOAc = 1 : 1). 1H NMR (300 MHz, CDCl3),
δ: 6.70 (s, 1 H, (HC=)arom); 6.57 (s, 1 H, (HC=)arom); 5.95 (d, 1 H,
CH=, J = 4.8 Hz); 5.86—5.83 (m, 3 H, OCH2O and CH=); 5.11
(br.s, 1 H, CHaHbC=O); 4.19 (br.s, 1 H, CHAr); 3.80 (d, 1 H,
CHaHbCHAr, J = 8.7 Hz); 3.20 (br.s, 1 H, CHaHbC=O); 2.89
(br.s, 1 H, CHaHbCHN); 2.19 (dd, 1 H, CHaHbCHAr, J = 9.1 Hz,
J = 13.5 Hz); 1.85—1.54 (m, 7 H, CHaHbCHN and 3 CH2).
13C NMR (75 MHz, CDCl3), δ: 175.02; 146.73; 146.23; 137.18;
133.89; 131.61; 128.61; 114.10; 109.90; 100.99; 69.69; 53.11;
46.14; 42.22; 41.13; 38.33; 23.47; 19.28. MS (70 eV, EI): m/z 297
[M+] (100); 268 (15); 227 (13); 214 (15); 213 (33); 200 (25);
199 (38); 190 (9); 185 (11); 183 (20); 178 (12); 177 (73); 173 (16);
169 (17); 155 (18); 153 (15); 141 (18); 115 (22); 97 (10); 77 (8).
Found (%): C, 72.67; H, 6.39; N, 4.78. C18H19NO3 (297.3).
Calculated (%): C, 72.71; H, 6.44; N, 4.71.
2,2ꢀDiallylꢀ1ꢀ[(6ꢀbromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)acetyl]azetꢀ
idine. Solid acyl chloride 4 (1.55 g, 5.6 mmol) was added in
portions to a mixture of 2,2ꢀdiallylazetidine (0.71 g, 5.2 mmol)
and 15% solution of NaOH (2.6 mL, 10 mmol) in CH2Cl2
(20 mL) with vigorous stirring at +10 °C (water bath). After the
addition was completed, the mixture was stirred for 20 min (TLC
monitoring, nꢀhexane : EtOAc = 1 : 1). After the reaction
reached completion, powdered K2CO3 was added and the susꢀ
pension was filtered through Celite, the filtrate was washed with
1 M aq. HCl, dried with Na2SO4, concentrated at reduced presꢀ
sure, the residue was dried in vacuo to obtain the amide (1.85 g,
94%) as a yellow oil, Rf = 0.34 (nꢀhexane : EtOAc = 4 : 1). Some
compound was recrystallized from nꢀhexane at –18 °C for eleꢀ
mental analysis, the crystals obtained melt back to an oil on
heating. Due to the hindered rotation in the amide group, doubling,
overlap, and broadening of some signals are observed in the NMR
spectra. 1H NMR (300 MHz, CDCl3), δ: 6.96 (s, 1 H, (HC=)arom);
6.87 and 6.84 (both s, total 1 H, (HC=)arom); 5.92 (s, 2 H,
OCH2O); 5.90—5.78 (m, 2 H, 2 CH=); 5.20—5.10 (m, 4 H,
2CH2=); 3.85 and 3.70 (both t, total 2 H, CH2N, J = 7.8 Hz);
3.49 and 3.37 (both s, total 2 H, CH2C=O); 2.82 and 2.66
(both dd, total 2 H, CH2 (in allyl), J = 6.6 Hz, J = 13.9 Hz,
J = 6.4 Hz, J = 14.2 Hz); 2.41 and 2.33 (both dd, total 2 H, CH2
(in allyl), J = 8.0 Hz, J = 14.4 Hz, J = 8.0 Hz, J = 13.9 Hz); 2.10
and 2.05 (both t, total 2 H, CH2C, J = 8.0 Hz, J = 7.8 Hz).
13C NMR (75 MHz, CDCl3), δ the major rotamer: 168.77; 147.41;
133.27; 127.69; 118.97; 114.72; 112.39; 111.25; 101.71; 71.02;
45.91; 41.52; 39.31; 22.76. MS (70 eV, EI): m/z 338/336
[M+ – C3H5] (2); 299 (23); 298 [M+ – Br] (100); 215/213 (30);
191 (12); 190 (99); 178 (10); 149 (9); 135 (11); 121 (16); 105 (8);
96 (44); 93 (15); 91 (16); 79 (22); 77 (19). Found (%): C, 57.24;
H, 5.38; N, 3.69; Br, 21.17. C18H20NO3Br (378.3). Calculatꢀ
ed (%): C, 57.15; H, 5.33; N, 3.70; Br, 21.12.
1
NMR spectra. H NMR (300 MHz, CDCl3), δ: 6.96 and 6.95
(both s, total 1 H, (HC=)arom); 6.85 and 6.78 (both s, total 1 H,
(HC=)arom); 5.92 (s, 2 H, OCH2O); 5.71 and 5.63 (both s, total
2 H, 2 CH=); 4.08 and 3.90 (both t, total 2 H, CH2N, J = 7.6 Hz);
2.41 and 3.37 (both s, total 2 H, CH2C=O); 3.21 and 3.04 (both d,
total 2 H, CH2CH=, J = 15.6 Hz, J = 16.8 Hz); 2.74 and 2.42
(both d, total 2 H, CH2CH=, J = 16.8 Hz, J = 15.6 Hz); 2.35
and 2.25 (both t, total 2 H, CH2C, J = 7.6 Hz). 13C NMR
(100 MHz, CDCl3), δ: 169.37; 168.48; 147.43; 147.04; 147.29;
147.23; 128.86; 128.31; 127.85; 115.12; 114.76; 112.48; 112.42;
111.12; 111.03; 101.70; 101.67; 73.48; 73.26; 47.19; 46.21; 43.89;
43.21; 40.08; 39.44; 33.21; 32.58. MS (70 eV, EI): m/z 351/349
[M+] (0.1); 271 (17); 270 (92); 260/258 (3); 241 (14); 215/213
(42); 192 (17); 190 (100); 162 (12); 135 (14); 91 (18); 79 (17);
78 (16); 77 (20); 51 (4). Found (%): C, 54.69; H, 4.78; N, 4.05;
Br, 22.67. C16H16NO3Br (350.2). Calculated (%): C, 54.87;
H, 4.61; N, 4.00; Br, 22.82.
Xꢀray diffraction study of compound 6a. Crystals C18H19NO4
(M = 313.34) are orthorhombic, the space group is P212121, at
T = 100.0(2) K, a = 8.3373(3) Å, b = 9.8045(5) Å, c = 17.9452(9)
Å, V = 1466.90(12) Å3, Z = 4, dcalc = 1.419 g cm–3, F(000) =
664, μ = 0.100 mm–1. Parameters of the unit cell and intensities
of 19109 reflections (4230 independent reflections, Rint = 0.039)
were measured on a Bruker SMART APEX II CCD automatic
threeꢀcircle diffractometer (λMoKαꢀirradiation, a graphite
monochromator, φꢀ and ωꢀscanning, 2θ = 60°). The structure
was solved by the direct methods and refined by the fullꢀmatrix
least squares method on F2 in anisotropic approximation for
nonhydrogen atoms. The hydrogen atom of the hydroxy group
was localized objectively in the differential Fourier syntheses
and refined in isotropic approximation with the fixed position
and thermal parameters (Uiso(H) = 1.2Ueq(O)). Position of the
rest of hydrogen atoms were calculated geometrically and reꢀ
fined in isotropic approximation with the fixed position (riding
model) and thermal parameters (Uiso(H) = 1.2Ueq(C)). The final
divergence factors are: R1 = 0.035 for 3948 independent reflecꢀ
tions with I ≥ 2σ(I) and wR2 = 0.088 for all the independent
reflections. The maximum and minimum values for the peaks of
3
residual electron density are equal to 0.329 and –0.289 e Å–
,
respectively. All the calculations were performed using the
SHELXTL program package.11 Tables of atom coordinates, bond
distances, bond and torsional angles, and anisotropic temperaꢀ
ture parameters for compound 6a were deposited with the Camꢀ
bridge Structural Database (CCDC 679405).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 08ꢀ03ꢀ00790),
the Council on Grants at the President of the Russian
Federation (Program of State Support of Young Russian
[(6ꢀBromoꢀ1,3ꢀbenzodioxolꢀ5ꢀyl)acetyl]ꢀ1ꢀazaspiro[3.4]ꢀ
octꢀ6ꢀene (5d). A Grubbs catalyst [Ru] (28 mg, 0.034 mmol,
1.0 mol.%) was added in two equal portions (each after 30 min)

8ꢀMembered Heck cyclization of azaspiroalkenes
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 7, July, 2010
1399
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Received January 11, 2010;
in revised form April 14, 2010