1,2-Disubstituted Alkenes as Migratory Insertion Participants in Zn(II)-Promoted Metalloamination/Cyclization of N,N-Dimethylhydrazinoalkenes

Article abstract of DOI:10.1021/acs.joc.6b01328

Diethylzinc-mediated metalloamination/cyclization of unsaturated N,N-dimethylhydrazines has been extended to the use of 1,2-disubstituted alkenes as N-Zn migratory insertion acceptors. Representative 2-arylethenes and vinylcyclopropanes readily serve as r

Full text of DOI:10.1021/acs.joc.6b01328

Brief Communication
pubs.acs.org/joc
1
,2-Disubstituted Alkenes as Migratory Insertion Participants in
Zn(II)-Promoted Metalloamination/Cyclization of
N,N‑Dimethylhydrazinoalkenes
Bryce Sunsdahl, Ky Mickelsen, Sean Zabawa, Bryon K. Anderson, and Tom Livinghouse*
Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717, United States
*
S Supporting Information
ABSTRACT: Diethylzinc-mediated metalloamination/cyclization of
unsaturated N,N-dimethylhydrazines has been extended to the use of
1
,2-disubstituted alkenes as N−Zn migratory insertion acceptors.
Representative 2-arylethenes and vinylcyclopropanes readily serve as
reaction participants in metalloamination/cyclization−allylation
cascades.
1
+
lassical intramolecular hydroamination of unsaturated
Reduction of the dimethylhydrazones (NaBH CN, H )
3
C
carbon−carbon bonds constitutes an efficient and atom-
economical method for the synthesis of nitrogenous hetero-
cycles. By definition, this process results in the simple delivery
of a hydrogen atom to the terminus of the carbon-based
addend. In contrast, metalloamination/cyclization leads to
consecutive N−C/C−metal bond formation, wherein the C−
M bond can subsequently be parlayed into new functionality.
Examples of the latter cascade reaction which involve the
catalytic utilization of organometallic intermediates derived
ultimately secured the substrate dimethylhydrazinoalkenes
5a−c (Scheme 1).
Cyclization Studies. We have previously shown that
various 2-arylethenyl substituents serve as viable participants
in hydroamination/cyclizations of primary alkenes catalyzed by
Scheme 1. Synthesis of Dimethylhydrazines
2
−4
5
6
7
8
from Pd(II),
Cu(II), Ir(III), Au(I), Rh(III), or the
9
10
stoichiometric use of Ti(IV) or Zn(II) intermediates have
1
1
appeared. The majority of catalytic metalloamination/
cyclizations involve organometallic or free-radical intermediates
that are fleeting in nature and are, therefore, synthetically
limited in the ultimate C−M bond functionalization step. We
have previously reported that N,N-dimethylhydrazinoalkenes
bearing monosubstituted alkenes undergo facile metalloamina-
tion/cyclization mediated by diethylzinc. Subsequent allylation
or acylation of the newly formed C−Zn bond, in situ, efficiently
provided the corresponding pyrrolidines or piperidines,
1
2
respectively. We now show that suitable 1,2-disubstituted
alkenes can serve as migratory insertion N−Zn acceptors in this
process.
The dimethylhydrazinoalkene substrates that were used in
this study were prepared in a manner analogous to the routes
12
we reported previously. Specifically, alkylation of the allylic
chlorides 1a and 1c with the lithioimine 2a followed by
immediate hydrolysis (H C O ) and dimethylhydrazone
2
2
4
formation (Me NNH ) furnished 3a and 3c. Alternatively,
2
2
Special Issue: Heterocycles
Received: June 1, 2016
alkylation of 1b with lithioisobutyronitrile 2b gave nitrile 4,
which upon reduction (DIBAL-H) and subsequent condensa-
tion of the crude aldehyde with Me NNH provided 3b.
2
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Brief Communication
1
3
complexes of the group 3 metals. We therefore began the
present investigation by examining the metalloamination/
cyclization of dimethylhydrazinoalkenes bearing this substituent
type. It was readily determined that migratory insertion
acceptors in this category are well suited for Zn(II)-mediated
metalloamination−allylation, with the stereochemical outcome
being very strongly governed by the influence of the
electronegativity of substituents at the 2-position. For example,
allylative cyclization of the simple phenyl-bearing hydrazine 5a
Scheme 3. Cyclization−Elimination of Dimethylhydrazine 5c
14
[
(1a) Et Zn (1.0 equiv), (1b) CuCN·2LiCl, 1-chloro-2-
methyl-2-propene (1.2 equiv)] provided the diastereomeric
2
dimethylhydrazines 6a and 6a as a 1:3 mixture in 79% isolated
a
s
yield. The stereochemical assignment for the major diaster-
eomer 6a is based on the substantial aromatic shielding effect
s
observed for its 4β-methyl substituent (0.52 ppm) compared to
the 4β-methyl (0.93 ppm) present in 6a . The corresponding 2-
chloro derivative 5aCl was considerably more selective in its
a
Scheme 4. Cyclization−Allylation of Dimethylhydrazine 5b
cyclization−allylation, favoring diastereomer 6a over 6aCls
Cla
(72%, de = 10:1). Moreover, analogous treatment of the 2-
fluoro-bearing substrate 5a provided superb stereoselectivity,
F
giving 6aFa (78%, de >20:1, Scheme 2). The origin of this
surprising stereoselectivity enhancement is under current
investigation.
Scheme 2. Cyclization−Allylation of Dimethylhydrazines 5a
In conclusion, diethylzinc-mediated metalloamination/cycli-
zation−allylation has been extended to encompass the
utilization of 1,2-disubstituted alkenes as migratory insertion
participants. Highly diastereoselective (de >20:1) C−N/C−C
difunctionalization in the 2-arylethane series is observed where
aryl is a 2-fluorophenyl substituent. The vinylcyclopropane
substituent confers high reactivity toward metalloamination
with concomitant scission of the cyclopropane ring. Intra-
molecular metalloamination involving a 3-(benzyloxy)-1(Z)-
propenyl substituent proceeds with initial cis → trans
isomerization followed by terminal elimination of EtZnOBn.
EXPERIMENTAL SECTION
■
General Remarks. Materials and Methods. Reactions employed
oven- or flame-dried glassware under nitrogen unless otherwise noted.
J. Young NMR experiments were performed under an argon
atmosphere, using standard Schlenk line techniques, or in an argon-
filled drybox. THF and diethyl ether were distilled from sodium/
benzophenone ketyl under nitrogen. Dichloromethane, diisopropyl-
amine, trifluoromethylbenzene, and toluene were distilled from CaH2
under nitrogen. Benzene and p-xylene were distilled from potassium
metal. All other materials were used as received from commercial
sources. Thin-layer chromatography (TLC) employed 0.25 mm glass
silica gel plates with UV indicator and were visualized with UV light
In an effort to elucidate the functional group compatibility of
metalloamination/cyclization, the cis-allylic ether bearing
dimethylhydrazinoalkene 5c was N-metalated with diethylzinc
at 90 °C. Under these conditions, cis → trans isomerization of
the alkene occurred rapidly prior to the metalloamination event.
In addition, β-elimination of the benzyloxy substituent proved
unavoidable, leading to the direct formation of pyrrolidine 9 in
(
254 nm) or potassium permanganate staining. Flash chromatographic
columns were hand-packed with silica gel 60 as a slurry in the initial
elution solvent. Nuclear magnetic resonance (NMR) data were
obtained at 300 or 500 MHz. Infrared spectra (IR) were obtained from
a FTIR-4100. High-resolution mass spectra (HRMS) were obtained
from TOF instrumentation. Infrared spectrum were recorded neat and
9
0% isolated yield after only 4 h (Scheme 3).
The utilization of vinylcyclopropanes as cyclization partic-
−1
ipants was subsequently investigated with the expectation that
cyclopropane C−C bond scission would provide a considerable
driving force for ring closure. It is therefore of considerable
interest that the vinylcyclopropane-bearing substrate 5b
underwent exceptionally facile cyclization with concomitant
cleavage of the cyclopropane ring to give the corresponding
allylation product 10 in excellent (92%) yield (Scheme 4). It
should be emphasized that the vinylcyclopropane “acceptor” is by
far the most reactive of the disubstituted alkenes that we have
examined to date.
are reported in cm .
(E)-2,2-Dimethyl-5-phenylpent-4-enal-N,N-dimethylhydrazone
(
3a). A 50 mL round-bottomed flask equipped with a magnetic stirring
bar, a reflux condenser, and an N inlet was charged with (E)-2,2-
2
1
5
dimethyl-5-phenylpent-4-enal (3.66 g, 19.4 mmol), and benzene (15
mL) was subsequently added. The reactant mixture was cooled to 0
°
C, and N,N-dimethylhydrazine (2.96 mL, 38.9 mmol) was added
dropwise via syringe. The reactant mixture was heated to reflux for 12
h. After cooling, the resulting mixture was dried with MgSO and
filtered through a pad of Celite. The crude product was purified by
bulb-to-bulb distillation (75 °C, 0.5 Torr) to afford 3.99 g (89%) of
4
B
DOI: 10.1021/acs.joc.6b01328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Brief Communication
1
the title compound as a clear oil. H NMR (500 MHz, DMSO-d ): δ
complete, the solution was chilled to 0 °C, quenched with methanol (5
6
7
1
1
.37 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.2 Hz,
H), 6.63 (s, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.26 (dt, J = 15.5, 7.7 Hz,
H), 2.74 (s, 6H), 2.34 (d, J = 6.7 Hz, 2H), 1.14 (s, 6H). 13C NMR
mL), and diluted with Et O (20 mL), and 1.0 M HCl was slowly
2
added until all of the precipitate was dissolved. The biphasic solution
was separated, and the aqueous layer was extracted with Et O (2 × 20
2
(
126 MHz, CDCl ): δ 146.3, 138.3, 132.6, 128.8, 127.8, 127.3, 126.4,
mL). The organic layers were combined, washed with brine (30 mL),
3
4
1
5.4, 43.8, 38.2, 26.5. IR (film): 3025, 2957, 2906, 2864, 2820, 2782,
dried over MgSO , and concentrated in vacuo. The crude aldehyde
was transferred into a 50 mL round-bottomed flask, equipped with a
4
−1
598, 1495, 1468, 1444, 1019, 966, 740, 693 cm . HRMS (ESI): calcd
+
for C H N [M + H] 231.1861, found 231.1883.
magnetic stirrer, and redissolved in dry CH Cl (25 mL). A small
15
22
2
2
2
(
E)-2-((E)-5-(2-Chlorophenyl)-2,2-dimethylpent-4-en-1-ylidene)-
amount of MgSO was added to the solution prior to the dropwise
4
1
,1-dimethylhydrazone (3a ). A 50 mL round-bottom flask equipped
addition of N,N-dimethylhydrazine (1.02 mL, 13.4 mmol) via syringe.
The reaction mixture was stirred for 2 h at 23 °C, diluted with dry
cl
with a magnetic stirring bar and an N2 inlet was charged with
diisopropylamine (0.981 mL, 7.00 mmol) followed by THF (10 mL).
The resulting mixture was cooled to 0 °C, n-butyllithium (2.21 mL,
Et O (20 mL), and filtered through a plug of Celite, washing with
2
Et O (3 × 15 mL). The solution was concentrated in vacuo and
2
3
3
1
.10 M in hexane) was added, and the solution was allowed to stir for
0 min at this temperature. A solution of N-tert-butyl-2-methylpropan-
-imine (0.890 g, 7.00 mmol) in THF (2 mL) was added dropwise via
purified via Kugelrohr distillation (75 °C at 1.0 Torr) from CaH to
2
1
provide the title compound (1.20 g, 92%) as a colorless oil. H NMR
(500 MHz, CDCl ): δ 6.52 (s, 1H), 5.45 (dt, J = 14.9, 7.4 Hz, 1H),
3
syringe, and the reaction mixture was warmed to room temperature.
4.98−4.87 (m, 1H), 2.73−2.60 (m, 6H), 2.11−1.94 (m, 2H), 1.32 (dt,
After 2 h, the resulting yellow solution was cooled to −78 °C, and (E)-
J = 9.0, 4.5 Hz, 1H), 0.99 (d, J = 8.1 Hz, 6H), 0.65−0.57 (m, 2H),
1
3
1-chloro-2-(3-chloroprop-1-en-1-yl)benzene (1.40 g, 7.50 mmol) was
0.30−0.23 (m, 2H). C NMR (126 MHz, CDCl ): δ 146.7, 136.6,
3
added dropwise via syringe. The reaction mixture was allowed to warm
to 23 °C and stirred at this temperature for 12 h. The resulting
homogeneous solution was diluted with ether (25 mL) and quenched
124.0, 44.6, 43.5, 37.4, 25.7, 24.6, 13.5, 6.4. IR (film): 3001, 2956,
2864, 1468, 1443, 1249, 1019, 963, 810, 587, 526 cm . HRMS (ESI):
calcd for C H N [M + H] 195.1862, found 195.1883.
−1
+
12
22
2
with NH Cl(aq) (10 mL). The organic layer was washed with brine
(E)-2-((Z)-6-(Benzyloxy)-2,2-dimethylhex-4-en-1-ylidene)-1,1-di-
methylhydrazone (3c). The title compound was synthesized by the
general method of hydrazone 3aCl utilizing N-tert-butyl-2-methyl-
propan-1-imine (1.09 g, 8.60 mmol) and (Z)-(((4-bromobut-2-en-1-
yl)oxy)methyl)benzene (2.29 g, 9.50 mmol) to yield (E)-2-((Z)-6-
4
(10 mL), dried with MgSO , and concentrated in vacuo. The crude
4
imine was immediately dissolved in THF (15 mL), and a solution of
oxalic acid (1.01 g, 8.00 mmol) in H O (5 mL) was added at room
temperature. The reaction mixture was allowed to stir for 2 h and
subsequently diluted with diethyl ether (25 mL). The organic layer
was washed with brine (10 mL), dried with MgSO , and concentrated
2
(benzyloxy)-2,2-dimethylhex-4-en-1-ylidene)-1,1-dimethylhydrazone
1
(1.58 g, 67%) as a clear oil. H NMR (500 MHz, CDCl
): δ 7.33 (d, J
4
3
in vacuo. The crude aldehyde was then dissolved in CH Cl (10 mL)
followed by N,N-dimethylhydrazine (0.841 g, 14.00 mmol) and
= 4.3 Hz, 4H), 7.29−7.25 (m, 1H), 6.49 (s, 1H), 5.71−5.57 (m, 2H),
2
2
4.49 (s, 2H), 4.06 (d, J = 6.1 Hz, 2H), 2.67 (s, 6H), 2.13 (d, J = 7.3
Hz, 2H), 1.03 (s, 6H). 13C NMR (126 MHz, CDCl
): δ 145.3, 138.4,
3
MgSO . The solution was allowed to stir for 4 h, filtered through a
4
plug of Celite, and concentrated in vacuo. The crude hydrazone was
131.2, 129.8, 129.0, 128.3, 127.9, 127.8, 127.5, 72.2, 66.0, 43.3, 39.1,
purified by column chromatography (5% EtOAc/Hex) to give (E)-2-
37.6, 26.0. IR (film): 2956, 2926, 2853, 1468, 1444, 1098, 1072, 1026,
1010, 735, 698 cm . HRMS (ESI): calcd for C17
275.2124, found 275.2115.
(E)-5-Cyclopropyl-2,2-dimethylpent-4-enenitrile (4). A 50 mL
round-bottomed flask equipped with a magnetic stirring bar and an
−1
H N
O [M + H]+
26 2
(
(E)-5-(2-chlorophenyl)-2,2-dimethylpent-4-en-1-ylidene)-1,1-dime-
1
thylhydrazone (1.13 g, 61%) as a clear oil. H NMR (500 MHz,
CDCl ): δ 7.47 (dd, J = 7.8, 1.8 Hz, 1H), 7.31 (dd, J = 7.9, 1.4 Hz,
3
1H), 7.17 (td, J = 7.5, 1.4 Hz, 1H), 7.12 (td, J = 7.6, 1.8 Hz, 1H), 6.73
(
(
d, J = 15.6 Hz, 1H), 6.57 (s, 1H), 6.19 (dt, J = 15.4, 7.6 Hz, 1H), 2.70
N inlet was charged with diisopropylamine (0.920 g, 9.09 mmol) and
2
s, 6H), 2.34 (dd, J = 7.5, 1.4 Hz, 2H), 1.10 (s, 6H). 13C NMR (126
THF (25 mL). The reaction mixture was cooled to 0 °C, and n-
butyllithium (3.03 mL, 3.0M, 9.09 mmol) was added dropwise via
syringe. The resulting solution was allowed to stir at this temperature
for 30 min and then cooled to −78 °C, isobutyronitrile (0.621 g, 9.00
mmol) was added dropwise via syringe, and the reaction mixture was
stirred for an additional 2 h at this temperature. A solution of (E)-(3-
chloroprop-1-en-1-yl)cyclopropane (1.19 g, 10.2 mmol) in THF (2
mL) was added all at once, and the reaction mixture was allowed to
slowly warm to 23 °C over 3 h. The reaction was quenched with
MHz, CDCl ): δ 145.5, 135.9, 132.5, 130.5, 129.5, 128.5, 127.8, 126.8,
3
1
1
2
26.6, 45.1, 43.40, 37.8, 26.2. IR (film): 2948, 2734, 1566, 1457, 1434,
+
251, 1025, 751. HRMS (ESI): calcd for C H ClN [M + H]
15
22
2
65.1472, found 265.1457.
E)-2-((E)-5-(2-Fluorophenyl)-2,2-dimethylpent-4-en-1-ylidene)-
,1-dimethylhydrazone (3a ). The title compound was synthesized
(
1
F
by the general procedure for hydrazone 3a , utilizing N-(tert-butyl)-2-
Cl
methylpropan-1-imine (1.00 g, 7.86 mmol) and (E)-1-(3-chloroprop-
1
-en-1-yl)-2-fluorobenzene (1.48 g, 8.65 mmol). The crude hydrazone
was purified by column chromatography (5% EtOAc/Hex) to give
E)-2-((E)-5-(2-fluorophenyl)-2,2-dimethylpent-4-en-1-ylidene)-1,1-
aqueous NH Cl (5 mL) and diluted with diethyl ether (25 mL). The
4
organic layer was washed with brine (10 mL), dried with MgSO , and
4
(
concentrated in vacuo. The crude nitrile was purified by column
1
dimethylhydrazine (1.13 g, 59%) as a clear oil. H NMR (500 MHz,
chromatography (5−15% EtOAc/Hex) to yield the title compound
1
CDCl ): δ 7.41 (td, J = 7.7, 1.8 Hz, 1H), 7.14 (ddd, J = 7.3, 5.4, 1.9
(1.52 g, 87%) as a clear oil. H NMR (500 MHz, CDCl ): δ 5.60−5.51
3
3
Hz, 1H), 7.05 (td, J = 7.5, 1.2 Hz, 1H), 6.99 (ddd, J = 10.9, 8.1, 1.2 Hz,
(m, 1H), 5.12 (ddt, J = 15.1, 8.6, 1.3 Hz, 1H), 2.20 (dd, J = 7.4, 1.2 Hz,
1
1
H), 6.58 (s, 1H), 6.52 (d, J = 16.0 Hz, 1H), 6.29 (dt, J = 16.0, 7.5 Hz,
2H), 1.44−1.38 (m, 1H), 1.32 (s, 6H), 0.76−0.67 (m, 2H), 0.38 (dt, J
13
13
H), 2.70 (s, 6H), 2.33 (dd, J = 7.5, 1.3 Hz, 2H), 1.10 (s, 6H).
C
= 6.4, 4.4 Hz, 2H). C NMR (126 MHz, CDCl ): δ 139.6, 125.0,
3
NMR (126 MHz, CDCl ): δ 159.9 (d, 1JC-F = 247.8), 145.6, 130.2,
120.9, 43.8, 32.6, 26.1, 13.5, 6.7. IR (film): 3005, 2987, 2933, 2234,
3
1
28.1, 128.0, 127.1, 124.5, 123.9, 115.7, 115.5, 45.4, 43.4, 37.8, 26.1. IR
1662, 1468, 1459, 1021, 966. HRMS (ESI): calcd for C H N [M +
H] 150.1283, found 150.1289.
(E)-2-((E)-(2,2-Dimethyl-5-phenylpent-4-en-1-yl)-1,1-dimethylhy-
drazine (5a). A 100 mL round-bottomed flask equipped with a
1
0
15
+
(film): 3040, 2957, 2922, 2864, 2782, 1486, 1468, 1229, 1020, 970,
−1
+
753 cm . HRMS (ESI): calcd for C H FN [M + H] 249.1768,
15
21
2
found 249.1746.
(
E)-2-((E)-5-Cyclopropyl-2,2-dimethylpent-4-en-1-ylidene)-1,1-di-
magnetic stirring bar and an N inlet was charged with hydrazone 3a
2
methylhydrazone (3b). A 100 mL multineck round-bottomed flask,
equipped with a magnetic stirrer, addition funnel, and rubber septum,
was flame-dried under vacuum and then backfilled with a nitrogen
atmosphere. The flask was charged with nitrile 4 (1.0 g, 6.7 mmol) and
dry CH Cl (25 mL) and then cooled to −78 °C for the dropwise
(0.60g, 2.60 mmol), and methanol (30 mL) was subsequently added.
Sodium cyanoborohydride (0.18g, 2.87 mmol) was added in one
portion, and the solution was titrated with HCl/MeOH (methyl
orange indicator, 20% v/v) until a light red color persisted. The
reactant mixture was stirred for 30 min, and the volatiles were removed
in vacuo. The crude salt was neutralized with aqueous NaOH (25% w/
v) to a pH of 11 and the crude product extracted with diethyl ether (3
2
2
addition of DIBAL-H (13.4 mL, 13.4 mmol, 1.0 M in hexanes) via the
addition funnel. The solution was allowed to stir at −78 °C for 1 h and
then slowly warmed to 23 °C over 3 h. Once the reaction was
× 10 mL). The organic layer was dried with MgSO , filtered through a
4
C
DOI: 10.1021/acs.joc.6b01328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Brief Communication
pad of Celite, and concentrated in vacuo. The crude product was
added. The reactant mixture was heated in a 90 °C oil bath until
metalloamination was complete (90% by H NMR, p-xylene as
internal standard). The volatiles were removed in vacuo, and THF (0.5
1
purfied by bulb to bulb distillation (75−80 °C, 0.5 Torr) to afford 0.52
1
g (85%) of the title compound. H NMR (500 MHz, CDCl ): δ 7.42
3
(
6
2
d, J = 7.2 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H),
mL) was introduced to the J. Young tube in an argon-filled drybox
14
.52 (d, J = 15.7 Hz, 1H), 6.43 (dt, J = 15.7, 7.5 Hz, 1H), 2.66 (s, 2H),
followed by the addition of a solution of CuCN·2LiCl in THF (150
μL, 1.0 M, 0.15 mmol). After 5 min, methallyl chloride (10.9 mg, 0.12
mmol)] was added, and the reactant mixture was kept at 23 °C for 2 h
.36 (s, 6H), 2.29 (d, J = 7.5 Hz, 2H), 1.78 (s, 1H), 1.07 (s, 6H). 13
C
NMR (126 MHz, CDCl ): δ 138.6, 132.8, 128.9, 128.0, 127.3, 126.6,
5
3
1
9.2, 47.9, 44.3, 35.3, 26.2. IR (film): 3197, 3025, 2949, 2835, 2764,
(or until the reaction was complete 95% H NMR). The Teflon screw
1
494, 1474, 1448, 966, 692 HRMS (ESI): calcd for C H N [M +
cap was removed, the reactant mixture was transferred to a 10 mL test
tube and diluted with diethyl ether (2.0 mL), and an aqueous solution
of NH Cl (satd) and NH /H O (1:1 v/v, 2 mL) was subsequently
added. The resulting suspension was vigorously stirred for 10 min until
the aqueous layer developed a deep blue color. The organic layer was
15
24
2
+
H] 233.2018, found 233.2045.
(
E)-2-(5-(2-Chlorophenyl)-2,2-dimethylpent-4-en-1-yl)-1,1-dime-
4
3
2
thylhydrazine (5a ). The title compound was synthesized by the
general reduction procedure of 5a utilizing hydrazone 3aCl (0.794 g,
3
Cl
.00 mmol) and NaBH CN (0.375 g, 6.00 mmol) to yield (E)-2-(5-(2-
removed and washed with a second portion of NH Cl (satd) and
3
4
chlorophenyl)-2,2-dimethylpent-4-en-1-yl)-1,1-dimethylhydrazine
NH /H O (1:1 v/v, 2 mL) followed by brine (2 mL) and dried with
3
2
1
(
0.640 g, 80%) as a clear oil. H NMR (500 MHz, CDCl ): δ 7.41 (td,
MgSO . The ether solution was then transferred to a 10 mL round-
3
4
J = 7.7, 1.8 Hz, 1H), 7.13 (tdd, J = 7.2, 5.1, 1.8 Hz, 1H), 7.04 (td, J =
.5, 1.3 Hz, 1H), 6.98 (ddd, J = 10.9, 8.1, 1.3 Hz, 1H), 6.52 (d, J = 15.9
Hz, 1H), 6.31 (dt, J = 15.6, 7.6 Hz, 1H), 2.58 (s, 2H), 2.45−2.38 (m,
bottomed flask equipped with a magnetic stirring bar and a N inlet
2
7
and cooled to 0 °C. Trifluoroacetic acid (13.7 mg, 0.12 mmol) was
added dropwise via a gastight syringe, and the reactant mixture was
allowed to stir for 1 h. The volatiles were removed in vacuo, and the
resultant viscous oil was triturated with pentane (3 × 1 mL) to afford
the trifluoroacetate salts 6.
13
6H), 2.16 (dd, J = 7.6, 1.3 Hz, 2H), 1.92 (s, 1H), 0.92 (s, 6H).
C
NMR (126 MHz, CDCl ): δ 130.5, 128.0, 127.9, 127.1, 124.3, 123.9,
3
1
1
2
15.7, 115.5, 58.7, 47.8, 44.2, 34.6, 25.8. IR (film): 2950, 2832, 1489,
−1
+
223, 979, 741 cm . HRMS (ESI): calcd for C H ClN [M + H]
N,N,4,4-Tetramethyl-2-(3-methyl-1-phenylbut-3-en-1-yl)-
15
23
2
66.1550, found 266.1562.
pyrrolidin-1-amine (6a). The title compound was isolated as a clear
1
(
E)-2-(5-(2-Fluorophenyl)-2,2-dimethylpent-4-en-1-yl)-1,1-dime-
oil (free base) (22.6 mg, 79%). H NMR (500 MHz, CDCl
3
): δ =
thylhydrazine (5a ). The title compound was synthesized by the
7.27−7.22 (m, 2H), 7.21−7.17 (m, 2H), 7.17−7.13 (m, 1H), 4.70−
4.61 (m, 1.5H), 3.39 (tt, J = 8.0, 3.6, 1H), 2.97 (td, J = 8.2, 4.3, 0.8H),
2.67 (d, J = 14.5, 0.3H), 2.61 (d, J = 8.0, 0.3H), 2.52 (dd, J = 14.3, 7.8,
0.8H), 2.44−2.40 (m, 1.5H), 2.37 (s, 6H), 2.34−2.30 (m, 1H), 1.69 (s,
2.2H), 1.65 (s, 0.8H), 1.28 (dd, J = 12.5, 8.9, 1H), 1.19−1.13 (m, 1H),
F
general reduction procedure of 5a utilizing hydrazone 3a (0.751 g,
F
3
.00 mmol) and NaBH CN (0.375 g, 6.00 mmol) to yield (E)-2-(5-(2-
3
fluorophenyl)-2,2-dimethylpent-4-en-1-yl)-1,1-dimethylhydrazine
1
(
0.668 g, 89%) as a clear oil. H NMR (500 MHz, CDCl ): δ 7.41 (td,
3
1
3
J = 7.7, 1.8 Hz, 1H), 7.13 (tdd, J = 7.2, 5.1, 1.8 Hz, 1H), 7.04 (td, J =
.5, 1.3 Hz, 1H), 6.98 (ddd, J = 10.9, 8.1, 1.3 Hz, 1H), 6.52 (d, J = 15.9
Hz, 1H), 6.31 (dt, J = 15.6, 7.6 Hz, 1H), 2.58 (s, 2H), 2.45−2.38 (m,
1.08 (s, 1H), 0.93 (s, 1H), 0.92 (s, 2H), 0.52 (s, 2H). C NMR (126
7
MHz, CDCl ): δ = 144.6, 129.9, 128.6, 127.9, 127.0, 125.7, 125.6,
3
111.5, 65.6, 63.4, 53.6, 52.8, 43.3, 43.2, 40.5, 39.8, 39.6, 38.7, 38.3,
1
3
6
H), 2.16 (dd, J = 7.6, 1.3 Hz, 2H), 1.92 (s, 1H), 0.92 (s, 6H).
C
34.9, 33.5, 30.6, 29.3, 29.2, 29.0, 22.7, 22.3. IR (film): 2938, 2863,
1
−1
NMR (126 MHz, CDCl ): δ 159.9 (d, J
= 248.1), 130.5, 128.0,
2812, 1452, 1181, 700, cm . HRMS (ESI): calcd for C H N [M +
3
C−F
19 31
2
+
1
27.9, 127.1, 124.3, 123.9, 115.7, 115.5, 58.7, 47.8, 44.2, 34.6, 25.8. IR
H] 287.2487, found 287.2566.
−
1
(film): 2952, 2837, 1486, 1455, 1229, 970, 753 cm . HRMS (ESI):
2-(1-(2-Chlorophenyl)-3-methylbut-3-en-1-yl)-N,N,4,4-tetra-
+
calcd for C H FN [M + H] 251.1924, found 251.1912.
methylpyrrolidin-1-amine (6aCl). The title compound was isolated
15
23
2
1
(E)-2-(5-Cyclopropyl-2,2-dimethylpent-4-en-1-yl)-1,1-dimethylhy-
as a mixture of diastereomers (1:10) (free base) (23.1 mg, 72%). H
drazine (5b). The title compound was synthesized by the general
reduction procedure of hydrazine 5a utilizing hydrazone 3b (0.988 g,
NMR (500 MHz, CDCl ): δ 7.27 (ddd, J = 13.7, 8.2, 1.7 Hz, 2H), 7.15
3
(td, J = 7.5, 1.4 Hz, 1H), 7.09−7.00 (m, 1H), 4.49 (s, 1H), 4.39 (s,
1H), 3.59 (ddd, J = 11.7, 7.5, 4.0 Hz, 1H), 3.02 (dt, J = 14.1, 5.4 Hz,
2H), 2.58 (d, J = 8.5 Hz, 1H), 2.52 (d, J = 8.4 Hz, 1H), 2.40 (s, 1H),
2.31 (s, 6H), 1.66 (s, 3H), 1.30−1.26 (m, 1H), 1.25−1.22 (m, 1H),
5
.00 mmol) and NaBH CN (0.628 g, 10.0 mmol) to yield (E)-2-(5-
3
cyclopropyl-2,2-dimethylpent-4-en-1-yl)-1,1-dimethylhydrazine (0.746
1
g, 76%) as a clear liquid. H NMR (500 MHz, CDCl ): δ 5.45 (dt, J =
3
1.07 (s, 3H), 0.93 (s, 3H). 13C NMR (126 MHz, CDCl ): δ 144.8,
15.1, 7.5 Hz, 1H), 4.92 (dd, J = 15.1, 8.4 Hz, 1H), 2.48 (s, 2H), 2.36
3
(
0
s, 6H), 1.84 (s, 2H), 1.30 (qt, J = 8.4, 4.8 Hz, 1H), 0.82 (s, 6H),
.65−0.54 (m, 2H), 0.26 (dt, J = 6.3, 4.2 Hz, 2H). C NMR (126
142.1, 134.7, 129.6, 129.16 126.5, 126.1, 111.2, 64.9, 53.2, 42.9, 40.8,
13
39.8, 34.5, 29.3, 28.7, 22.5. IR (film): 2952, 2865, 2844, 1472, 1441,
−1
H29ClN
[M + H]+
2
MHz, CDCl ): δ 136.2, 124.3, 58.5, 47.7, 43.3, 34.0, 25.6, 24.6, 13.5,
6
6
1025, 884, 750 cm . HRMS (ESI): calcd for C19
321.2098, found 321.2101.
3
.3. IR (film): 3017, 2921, 2722, 1423, 1402, 1319, 1021, 953, 818,
−1
+
35, 562 cm . HRMS (ESI): calcd for C H N [M + H] 197.2018,
2-(1-(2-Fluorophenyl)-3-methylbut-3-en-1-yl)-4,4-N,N-tetra-
methylpyrrolidin-1-amine (6a ). The title compound was isolated
as a clear oil (free base) (23.7 mg, 78%). H NMR (500 MHz,
CDCl ): δ 7.17 (td, J = 7.5, 1.8 Hz, 1H), 7.11 (tdd, J = 7.3, 5.1, 1.8 Hz,
12
24
2
found 197.2033.
F
1
(
Z)-2-(6-(Benzyloxy)-2,2-dimethylhex-4-en-1-yl)-1,1-dimethylhy-
drazine (5c). The title compound was synthesized by the general
reduction method of hydrazine 5a utilizing hydrazone 3c (1.00 g, 3.64
mmol) and NaBH CN (0.458 g, 7.29 mmol) to yield (Z)-2-(6-
3
1H), 7.01 (td, J = 7.5, 1.3 Hz, 1H), 6.94 (ddd, J = 10.9, 8.1, 1.3 Hz,
1H), 4.55 (d, J = 10.8 Hz, 2H), 3.50 (dd, J = 10.6, 5.7 Hz, 1H), 3.10−
2.98 (m, 1H), 2.76 (dd, J = 14.4, 5.8 Hz, 1H), 2.52−2.38 (m, 3H),
2.39−2.29 (m, 6H), 1.65 (s, 3H), 1.34 (dd, J = 12.8, 8.7 Hz, 1H),
3
(
benzyloxy)-2,2-dimethylhex-4-en-1-yl)-1,1-dimethylhydrazine (0.916
1
g, 91%) as a clear oil. H NMR (500 MHz, DMSO): δ 7.33 (q, J = 3.9,
2
13
.9 Hz, 4H), 7.26 (ddd, J = 7.3, 4.9, 2.3 Hz, 1H), 5.72−5.60 (m, 2H),
.50 (s, 2H), 4.07 (d, J = 5.8 Hz, 2H), 2.51 (s, 2H), 2.38 (s, 6H), 1.99
1.27−1.19 (m, 1H), 0.93 (s, 3H), 0.77 (s, 3H). C NMR (126 MHz,
CDCl ): δ 161.5 (d, 1JC-F = 244.1), 144.6, 131.2, 129.9, 127.1, 123.1,
4
(
3
d, J = 7.0 Hz, 2H), 1.86 (s, 1H), 0.86 (s, 6H). 13C NMR (126 MHz,
115.1, 115.0, 111.3, 64.0, 53.0, 41.1, 40.4, 39.8, 34.1, 29.2, 28.9, 22.2.
CDCl ): δ 138.4, 130.1, 128.3, 127.9, 127.8, 127.5, 127.5, 72.2, 65.9,
5
1
IR (film): 3072, 2950, 2865, 2770, 1648, 1582, 1489, 1453, 1222, 886,
3
−1
+
8.6, 47.7, 37.7, 34.4, 25.6. IR (film): 2956, 2926, 2853, 1468, 1444,
754 cm . HRMS (ESI): calcd for C19
found 305.2357.
H30FN [M + H] 305.2394,
2
−1
098, 1072, 1026, 1010, 735, 698 cm . HRMS (ESI): calcd for
+
C H N O [M + H] 277.2281, found 277.2276.
N,N,4,4-Tetramethyl-2-vinylpyrrolidin-1-amine (9). The title
17
28
2
1
Synthesis of Cyclic Hydrazines. General Procedure for
compound was isolated as a clear oil (TFA salt) 25.4 mg (90%). H
CuCN-Mediated Allylation of Metalloamination Intermediates.
NMR (500 MHz, CDCl ): δ 5.84 (ddd, J = 17.2, 10.2, 8.4 Hz, 1H),
3
In an argon-filled glovebox, ZnEt in p-xylene (50 μL, 2.0 M, 0.10
5.36−5.22 (m, 2H), 3.81 (q, J = 8.3 Hz, 1H), 3.16 (d, J = 8.8 Hz, 1H),
2
mmol) and toluene or (trifluoromethyl)benzene (0.5 mL) were
introduced into a J. Young NMR tube equipped with a Teflon screw
cap, and hydrazinoalkene (5a−c) (0.10 mmol) was subsequently
2.95 (s, 6H), 2.81 (d, J = 8.8 Hz, 1H), 1.92 (dd, J = 13.1, 8.0 Hz, 1H),
1
3
1.62 (dd, J = 13.1, 8.5 Hz, 1H), 1.16 (s, 3H), 1.13 (s, 3H). C NMR
(126 MHz, CDCl ): δ 136.2, 119.8, 64.9, 60.9, 45.0, 42.0, 35.0, 29.1,
3
D
DOI: 10.1021/acs.joc.6b01328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Brief Communication
−
1
2
8.5. IR (film): 2966, 2876, 1781, 1670, 1200, 1164, 796, 704 cm .
(12) Sunsdahl, B.; Smith, A. R.; Livinghouse, T. Angew. Chem., Int.
Ed. 2014, 53, 14352−14356.
+
HRMS (ESI): calcd for C H N [M + H] 169.1705, found
10
20
2
169.1731.
(13) (a) Jiang, T.; Huynh, K.; Livinghouse, T. Synlett 2013, 24, 193−
196. (b) Jiang, T.; Livinghouse, T.; Lovick, H. M. Chem. Commun.
2011, 47, 12861−12863.
(
E)-N,N,4,4-Tetramethyl-2-(6-methylhepta-1,6-dien-1-yl)-
pyrrolidin-1-amine (10). The title compound was isolated as a clear
1
oil (TFA salt) 33.5 mg (92%). H NMR (500 MHz, CDCl ): δ 5.79−
(14) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
3
5
4
(
(
1
.70 (m, 1H), 5.48 (dd, J = 15.4, 8.6 Hz, 1H), 4.70−4.65 (m, 1H),
.65−4.60 (m, 1H), 3.83−3.73 (m, 1H), 3.18 (d, J = 9.1 Hz, 1H), 2.90
1
(
988, 53, 2390−2392.
15) Jarboe, S. G.; Beak, P. Org. Lett. 2000, 2, 357−360.
d, J = 5.1 Hz, 6H), 2.79 (d, J = 9.1 Hz, 1H), 2.06−1.95 (m, 4H), 1.87
dd, J = 13.1, 7.5 Hz, 1H), 1.71−1.66 (m, 3H), 1.66−1.60 (m, 2H),
13
.52−1.45 (m, 2H), 1.16 (s, 3H), 1.13 (s, 3H). C NMR (126 MHz,
CDCl ): δ 145.3, 137.0, 127.2, 110.1, 64.9, 60.2, 45.1, 41.6, 37.2, 34.7,
3
3
1
1.6, 29.2, 28.8, 26.5, 22.2. IR (film): 2966, 2936, 2873, 1780, 1670,
−1
652, 1463, 1202, 1168, 704 cm . HRMS (ESI): calcd for C H N
16
30
2
+
[
M + H] 251.2120, found 251.2163.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01328.
1H and 13C NMR spectra for all newly synthesized
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: livinghouse@chemistry.montana.edu.
■
*
Notes
The authors declare no competing financial interest.
REFERENCES
■
(
1) (a) For a recent comprehensive review of hydroamination/
cyclization, see: Hannedouche, J.; Schulz, E. Chem. - Eur. J. 2013, 19,
4
972−4985. (b) A hydroamination of aminoolefins and aminoalkynes
employing catalytic zinc has appeared: Pissarek, J.-W.; Schlesiger, D.;
Roesky, P. W.; Blechert, S. Adv. Synth. Catal. 2009, 351, 2081−2085.
(
2) (a) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132, 12157−
12159 and references cited therein. (b) Nicolai, S.; Sedigh-Zadeh, R.;
Waser, J. J. Org. Chem. 2013, 78, 3783−3801. (c) Nicolai, S.;
Piemontesi, C.; Waser, J. Angew. Chem., Int. Ed. 2011, 50, 4680−4683.
(
3) (a) Hoover, J. M.; DiPasquale, A.; Mayer, J. M.; Michael, F. M. J.
Am. Chem. Soc. 2010, 132, 5043−5053. (b) Hewitt, J. F. M.; Williams,
L.; Aggarwal, P.; Smith, C. D.; France, D. J. Chem. Sci. 2013, 4, 3538−
3
3
(
543. (c) Cernak, T. A.; Lambert, T. H. J. Am. Chem. Soc. 2009, 131,
124−3125.
4) (a) White, D. R.; Hutt, J. T.; Wolfe, J. P. J. Am. Chem. Soc. 2015,
1
37, 11246−11249. (b) Faulkner, A.; Scott, J. S.; Bower, J. F. J. Am.
Chem. Soc. 2015, 137, 7224−7230. (c) Jana, R.; Pathak, T. P.; Jensen,
K. H.; Sigman, M. S. Org. Lett. 2012, 14, 4074−4077.
(
5) (a) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 8069−
8
077. (b) Turnpenny, B. W.; Chemler, S. R. Chem. Sci. 2014, 5, 1786−
1793 and references cited therein.
(
9
(
6) Choi, G. J.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226−
229.
7) Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010,
1
(
(
32, 1474−1475.
8) Piou, T.; Rovis, T. Nature 2015, 527, 86−90.
9) (a) McGrane, P. L.; Jensen, M.; Livinghouse, T. J. Am. Chem. Soc.
1
992, 114, 5459−5460. (b) McGrane, P. L.; Livinghouse, T. J. Am.
Chem. Soc. 1993, 115, 11485−11489.
10) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett.
006, 8, 2803−2805 and references cited therein. (b) Yin, Y.; Ma, W.;
Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731−5736.
11) A consecutive C−N/C−C functionalization of alkenes not
(
2
(
involving organometallic intermediates has appeared: Ivanovich, R. A.;
Clavette, C.; Vincent-Rocan, J.-F.; Roveda, J.-G.; Gorelsky, S. I.;
Beauchemin, A. M. Chem. - Eur. J. 2016, 22, 7906−7916.
E
DOI: 10.1021/acs.joc.6b01328
J. Org. Chem. XXXX, XXX, XXX−XXX