Novel cleavage of propargylamines by reaction with organolithium compounds

Article abstract of DOI:10.1021/jo960025+

Treatment of secondary aliphatic 2-bromoallylamines with an excess of an organolithium compound led to saturated amines in which the organic group of the organolithium compound is incorporated at the α carbon. On the other hand, the successive reaction of the former amines with BuLi and t-BuLi between -80°C and rt gave 1,3-diamines or hexahydropyrimidines depending on the reaction time. The formation of these unexpected products involves initial generation of lithium propargylamides, which subsequently undergo cleavage of the C propargylic-C acetylenic bond induced by the organolithium present in each case in the reaction medium. A mechanism which takes into account all the different reaction products has been proposed and additionally supported by successful trapping of dilithium acetylide.

Full text of DOI:10.1021/jo960025+

3646
J . Org. Chem. 1996, 61, 3646-3649
Novel Clea va ge of P r op a r gyla m in es by Rea ction w ith
Or ga n olith iu m Com p ou n d s
J ose´ Barluenga,* Rosa-Mar´ıa Canteli, and J osefa Flo´rez
Instituto Universitario de Quı´mica Organometa´lica “Enrique Moles”, Unidad Asociada al C.S.I.C.,
Universidad de Oviedo, J ulia´n Claverı´a 8, 33071 Oviedo, Spain
Received J anuary 2, 1996X
Treatment of secondary aliphatic 2-bromoallylamines with an excess of an organolithium compound
led to saturated amines in which the organic group of the organolithium compound is incorporated
at the R carbon. On the other hand, the successive reaction of the former amines with BuLi and
t-BuLi between -80 °C and rt gave 1,3-diamines or hexahydropyrimidines depending on the reaction
time. The formation of these unexpected products involves initial generation of lithium propar-
gylamides, which subsequently undergo cleavage of the C propargylic-C acetylenic bond induced
by the organolithium present in each case in the reaction medium. A mechanism which takes into
account all the different reaction products has been proposed and additionally supported by
successful trapping of dilithium acetylide.
Sch em e 1
Previous studies in these laboratories showed that
successive treatment of 2-bromoallylamine 1 with butyl-
lithium (1 equiv) and tert-butyllithium (2 equiv) in ether
at -110 °C led, after quenching with D2O at -110 °C, to
an 1:3 mixture of 2-deuterioallylamine 2 and propargyl-
amine 3, respectively1 (Scheme 1). The later and major
product is formed in the first step due to decomposition
of the lithium amide intermediate 4 by elimination of
hydrogen bromide. In an attempt to address this reaction
to the formation of propargylamine 3 as the only reaction
product, it was decided to carry out the experiment either
with an excess of BuLi at room temperature, or as
indicated in Scheme 1, but allowing the reaction mixture
to achieve rt after each organolithium addition. The
results of these experiments, which were absolutely
unexpected, gave rise to this study; and we now report
on a novel cleavage of the CR-Câ bond of propargyl-
amines by the action of organolithium compounds, which
led to saturated secondary amines or 1,3-diamine deriva-
tives depending on the reaction conditions.
Sch em e 2
As far as we know, the only precedent of this cleavage
reaction has been reported for primary propargylamine
5a 2a (Scheme 2). Analogously, lithiated primary amines
5b having tertiary organic groups have been proposed
to undergo ready C-C bond fragmentation on heating
with an excess of an organolithium compound which led
to formation, among several other reaction products, of
R-substituted primary amines.2b Other related prece-
dents to this almost unknown displacement-induced CR-
Câ heterolytic fragmentation of lithium propargylamides
in the presence of alkyllithium derivatives can be found
in the case of substrates 6-9 shown in Scheme 2.
R-Aminoacetophenone oxime derivatives 6 undergo nu-
cleophilic substitution at the R carbon atom by strong
nucleophiles with formation of benzonitrile, which rep-
resents an example of displacement-induced fragmenta-
tion.3 The instability of R-tosylamino acid chlorides 7 in
the presence of bases is interpreted in terms of a scission
of the R,â carbon-carbon bond in the sulfonamido anion.4
Tertiary γ-haloamines 8 can undergo heterolytic frag-
mentation under solvolytic conditions with release of an
iminium ion and an olefin.3,5 In this context, the reaction
of tertiary 1,2-amino alcohols 9 with lead tetraacetate,
which involves cleavage of the C-C bond by a mechanism
that has been shown to proceed via the iminium ion,6 or
the photoinduced C-C bond cleavage via electron-transfer
reactions of some substituted tertiary amines 9, which
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Barluenga, J .; Canteli, R. M.; Flo´rez, J . J . Org. Chem. 1994, 59,
602.
(2) (a) Richey, H. G., J r.; Erickson, W. F. J . Org. Chem. 1983, 48,
4349. (b) Richey, H. G., J r.; Cabre´, S. J . Org. Chem. 1983, 48, 3822.
(3) Becker, K. B.; Grob, C. A. The Formation of Unsaturated Groups
by Heterolytic Fragmentation. In The Chemistry of Functional Groups;
Patai, S., Ed.; Wiley: London, 1977; Supp. A, p 653.
(4) (a) Wiley, R. H.; Davis, R. P. J . Am. Chem. Soc. 1954, 76, 3496.
(b) Beecham, A. F. J . Am. Chem. Soc. 1957, 79, 3257.
(5) Grob, C. A. Angew. Chem. 1969, 81, 543; Angew. Chem., Int. Ed.
Engl. 1969, 8, 535.
S0022-3263(96)00025-4 CCC: $12.00 © 1996 American Chemical Society

Novel Cleavage of Propargylamines
J . Org. Chem., Vol. 61, No. 11, 1996 3647
Sch em e 3
Sch em e 4
Ta ble 1. Rea ction of 1 w ith a n Excess of Bu tyllith iu m
Sch em e 5
no. eq
entry of BuLi
yield
T (°C)
t
product ratioa
(%)b
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
3
3
3
20
20
0
-15
-30
-80
4 h
10
10
10, 3
3
95
97
94
55
65
50
73
74
74
15 min
1 min
5 min
2 h
2:1
3
1 h
11c
10
10
3
-80 to 20 12 h
-80 to 20 90 min
-80
30 min
a
1
b
Product ratio determined by H NMR. Isolated yields based
on compound 1. c The reaction was quenched with D2O; degree of
deuteration >95%.
leads to a neutral free radical and an iminium ion,7 can
also be included.
amine 10. In addition, phenyllithium (5 equiv, rt)
efficiently reacted with 2-bromoallylamine 1 in an analo-
gous way to BuLi yielding N-butylbenzylamine (13).
The results presented here may be explained in terms
of the mechanism put forth in Scheme 5. As above
noticed lithium amide 4 is unstable and decomposes
spontaneously, probably by intramolecular elimination
of HBr, to 3, which undergoes further dilithiation with
the excess of alkyllithium present in the reaction
medium to give dianion 14. Under these reaction condi-
tions γ-nitrogen-functionalized organolithium compound
14 is stable at low temperatures (ca. -80 to -15 °C), but
at temperatures close to 0 °C or rt undergoes a subse-
quent heterolytic cleavage of the propargylic carbon-
acetylenic carbon σ-bond with displacement of 1,2-
dilithioethyne induced by a molecule of alkyllithium to
furnish lithium amide 16. Presumably, this fragmenta-
tion reaction could take place through complex 15 formed
by bonding between the electron pair of the amide group
and the lithium atom of the organolithium RLi as well
as the possible intramolecular complexation of the triple
bond π-system with the lithium amide. This complex 15
places the organolithium in the proximity of the pro-
pargylic carbon in which may be considered as an
example of a CIPE process.8 The formation of acetylene
after hydrolysis was verified by trapping the 1,2-dilithio-
ethyne with benzaldehyde, which was added to the
reaction mixture before hydrolysis as shown in Scheme
6. In this reaction a nearly equimolecular amount of 1,4-
diol 17 was obtained in addition to amine 10. This result
lends strong support to the above-postulated mechanism.
B. Rea ction s of 2-Br om oa llyla m in es w ith Bu Li
a n d t-Bu Li a t Rt. As depicted in Scheme 7, the
Resu lts a n d Discu ssion
A. Rea ction s of 2-Br om oa llyla m in es w ith Excess
of Alk yllith iu m s. The reaction between aliphatic sec-
ondary 2-bromoallylamine 1 and butyllithium (5 equiv)
at rt, unexpectedly led, after hydrolysis, to N-butylpent-
ylamine (10) as the sole product instead of the initially
foreseen propargylamine 3 (Scheme 3). In order to
understand this transformation 2-bromoallylamine 1 was
treated with butyllithium under several reaction condi-
tions with variations in stoichiometry, temperature and
time, and the results are presented in Table 1. The
reaction of 1 with 5 equiv of BuLi is indeed very fast and
after 15 min at rt the selective formation of 10 was
observed almost quantitatively (entry 2). If, however, the
reaction is carried out at 0 °C and quenched after 1 min
a mixture of saturated amine 10 and propargylamine 3
is isolated in a 2:1 ratio respectively (entry 3). On the
other hand, this treatment afforded exclusively proparg-
ylamine 3 or its deuterated derivative 11 (formed after
quenching with D2O) when the reaction was run at lower
temperatures (-15, -30, -80 °C; entries 4-6). The same
reaction conducted with 3 equiv of BuLi provided identi-
cal results (entries 7-9), indicating likewise, that pro-
pargylamine 3 derivatives are intermediates in the
transformation of allylamine 1 to saturated amine 10.
This was proved in an independent experiment in which
N-butylpropargylamine (3) was converted into amine 10
by treatment with BuLi (5 equiv) at rt (Scheme 4).
Furthermore, substituted 2-bromoallylamine 12 under-
went under similar experimental conditions, an analo-
gous transformation furnishing the same saturated
(6) Gladych, J . M. Z.; Hartley, D. Polyfunctional Amines. In Com-
prehensive Organic Chemistry; Barton, D. H. R., Ollis, W. D., Eds.;
Pergamon: Oxford, 1979; Vol. 2, p 61.
(7) Lee, L. Y. C.; Ci, X.; Giannotti, C.; Whitten, D. G. J . Am. Chem.
Soc. 1986, 108, 175.
(8) (a) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (b)
Although the formation of free CH2dNBu cannot be ruled out, picture
15 could be a better model for the fragmentation reaction, given that
organolithium 14 is stable at rt (does not decompose by â-elimination)
in the absence of any other organolithium compound.

3648 J . Org. Chem., Vol. 61, No. 11, 1996
Barluenga et al.
Sch em e 6
Sch em e 8
Sch em e 7
were further confirmed by comparison with authentic
materials prepared from 3-chloro-2-(chloromethyl)-1-pro-
pene and the corresponding aliphatic amine11 to give 18
and 21, which subsequently were treated with aqueous
formaldehyde12 to yield 19 and 22 (Scheme 8).
These results are readily rationalized by invoking an
analogous mechanism to the previously proposed in
Scheme 5. At rt the cleavage of the lithium propargy-
lamide generated in the reaction medium could be
promoted by formation of complex 23 with the simulta-
neously originated vinylic organolithium compound to
give 1,3-diamines 18 and 21 after hydrolysis (Scheme 7).
On longer reaction times complex 24 would account for
the generation of hexahydropyrimidine 19 through acy-
clic aminal intermediate 25. The transformation of
acyclic 1,3-diamines 18 and 21 to the corresponding cyclic
diamines 19 and 22 observed in the purification process,
could be attributed to the presence in the crude reaction
products of some formaldehyde derivative (ca. CH2dNR,
maybe as a trimer) formed in the cleavage process.
In summary, we have found that lithium propargyla-
mides generated in situ from secondary aliphatic 2-bro-
moallylamines either by treatment with an excess of an
organolithium compound at rt or by successive reaction
with a stoichiometric amount of BuLi and then t-BuLi
between -80 °C and rt, undergo a novel C-C cleavage
reaction with elimination of the corresponding lithium
acetylide. This displacement-induced fragmentation led
to amine derivatives, which respectively incorporate into
their structure the organic group of the organolithium
used as reagent or the â-nitrogen-functionalized vinylic
organolithium compound simultaneously formed in the
reaction medium. The successful trapping of dilithium
acetylide with benzaldehyde provides evidence for the
postulated mechanism.
successive reaction of 2-bromoallylamine 1 with BuLi (1
equiv) and t-BuLi (2 equiv) between -80 °C and rt yielded
a mixture of compounds 18 and 19. The ratio of these
products was found to be significantly dependent on the
reaction time with t-BuLi. Thus, 1,3-diamine 18 was the
major product observed at shorter reaction times, while
the hexahydropyrimidine 19 was formed as the major
product on longer reaction times. Under identical condi-
tions, 2-bromoallylamine 20 afforded exclusively 1,3-
diamine 21. In this reaction the formation of the
corresponding hexahydropyrimidine 22 was not detected
even after 12 h at rt with t-BuLi.9 However, partial
transformation of 21 to 22 occurred during silica gel
column chromatography and this conversion was com-
plete when purification of 1,3-diamine 21 was attempted
by distillation (0.001 mmHg) or when a THF solution of
crude 21 was refluxed for 12 h.10 The structure of these
compounds was established by 1H and 13C NMR spec-
troscopy and in the case of product 19 two-dimensional
Exp er im en ta l Section
Gen er a l. General experimental techniques and analytical
measurements were applied as previously described.1 The
preparation of 2-bromoallylamines 1 and 20 was reported
previously.1 Similarly prepared was (Z)-2-bromo-N-butyl-2-
butenylamine1 (12) from (Z)-1,2-dibromo-2-butene and spectral
data appear in the supporting information. PhLi was prepared
according to the published procedure.13 The level of purity of
compounds is indicated by the inclusion of copies of NMR
spectra presented in the supporting information.
Gen er a l P r oced u r e for th e Rea ction of 2-Br om oa llyl-
a m in es w ith Excess of a n Alk yllith iu m . To a solution of
the corresponding 2-bromoallylamine 1 or 12 (5 mmol) in Et2O
(30 mL) was added dropwise BuLi (2.5 M in hexane, 25 mmol
or 15 mmol) or PhLi (1.25 M in ether, 25 mmol). The resulting
solution was stirred at the temperature and for the time
indicated in Table 1 or Scheme 4 for each particular case. The
reaction mixture was hydrolyzed with H2O and extracted with
1
n
proton to carbon correlations through J CH and J CH
experiments were also carried out. Moreover, given the
unexpected nature of these compounds their structures
(9) A factor which may contribute to this difference may have to do
with the larger size of benzyl group compared to butyl group.
(10) The partial conversion of diamine 18 to hexahydropyrimidine
19, although was observed in some cases upon silica gel column
chromatography or during distillation (0.001 mmHg), seems to be a
much less favored process.
(11) D'Amico, J . J .; Harman, M. W.; Cooper, R. H. J . Am. Chem.
Soc. 1957, 79, 5270.
(12) Barluenga, J .; Olano, B.; Fustero, S. J . Org. Chem. 1985, 50,
4052.
(13) Nobis, J . F.; Moormeier, L. F. Ind. Eng. Chem. 1954, 46, 539.

Novel Cleavage of Propargylamines
J . Org. Chem., Vol. 61, No. 11, 1996 3649
ether. The organic phase was dried and concentrated in vacuo
(15 mmHg), and the resulting crude material was purified by
distillation (bp is given at the corresponding pressure). Yields
are listed in Table 1 and Scheme 4. The following compounds
were prepared according to this method.
Gen er a l P r oced u r e for th e Rea ction of 2-Br om oa llyl-
a m in es w ith Bu Li a n d t-Bu Li a t Rt. To a solution of the
corresponding 2-bromoallylamine 1 or 20 (5 mmol) in ether
(30 mL) cooled at -80 °C was added dropwise BuLi (2.5 M in
hexane, 5 mmol). The resulting solution was stirred for 30
min at -80 °C and then 30 min at rt. After the solution was
cooled again to -80 °C, t-BuLi (1.7 M in pentane, 10 mmol)
was added. The mixture was stirred for 1-12 h (the reaction
time for each case is indicated in Scheme 7); allowing the
temperature to reach rt. The reaction mixture was hydrolyzed
with H2O and extracted with ether. The organic phase was
dried and concentrated in vacuo, and the resulting crude
material was purified by distillation (in this case bp is given
at the corresponding pressure) or flash column chromatogra-
phy (in this case Rf is reported with the eluent solvent used
in the column). The following compounds were prepared
according to this method.
N-Bu tylp en tyla m in e (10):14 Colorless liquid; distilled trap
1
to trap at rt, 0.1 mmHg; H NMR δ 0.89 (m, 6H), 1.25-1.55
(m, 11H), 2.57 (m, 4H); 13C NMR δ 13.4, 20.0, 22.1, 29.1, 29.3,
31.8, 49.3, 49.6; MS m/ z 143 (M+, 4), 100 (70), 86 (100), 44
(82).
N-Bu tylp r op a r gyla m in e (3): Colorless liquid; distilled
trap to trap at rt, 0.1 mmHg; 1H NMR δ 0.90 (t, J ) 7.2, 3H),
1.25-1.55 (m, 4H), 1.75 (br s, 1H), 2.20 (t, J ) 2.5, 1H), 2.67
(t, J ) 7, 2H), 3.41 (m, 2H); 13C NMR δ 14.2, 20.6, 32.1, 38.3,
48.5, 71.4, 82.5; MS m/ z 111 (M+, 2), 69 (17), 68 (100), 41 (8).
N-Bu tyl-3-d eu ter iop r op a r gyla m in e (11): Colorless liq-
uid; distilled trap to trap at rt, 0.1 mmHg; 1H NMR δ 0.90 (t,
J ) 7.2, 3H), 1.25-1.55 (m, 4H), 1.75 (br s, 1H), 2.67 (t, J )
7, 2H), 3.41 (s, 2H); 13C NMR δ 14.2, 20.6, 32.1, 38.3, 48.5,
71.4 (t, J ) 39), 82.5 (t, J ) 7.3); MS m/ z 112 (M+, 13), 111
(65), 110 (100), 109 (68).
N,N′-Dibu tyl-2-m eth ylen e-1,3-pr opan ediam in e (18): Yel-
low oil; bp 67-69 °C, 0.1 mmHg; 1H NMR δ 0.89 (t, J ) 7,
6H), 1.25-1.55 (m, 8H), 1.75 (br s, 2H), 2.56 (t, J ) 7.2, 4H),
3.24 (s, 4H), 4.99 (s, 2H); 13C NMR δ 13.9, 20.4, 32.1, 49.0,
53.6, 111.5, 145.9; MS m/ z 198 (M+, <1), 125 (100), 82 (56).
N,N′-Diben zyl-2-m eth ylen e-1,3-p r op a n ed ia m in e (21):
Colorless oil; Rf 0.28 (CH3OH); 1H NMR δ 1.95 (br s, 2H), 3.33
(s, 4H), 3.78 (s, 4H), 5.1 (s, 2H), 7.3 (m, 10H); 13C NMR δ 52.8,
53.1, 112.2, 126.8, 128.0, 128.2, 140.2, 145.6.
N-Bu tylben zyla m in e (13):15 Colorless liquid; bp 69-71 °C,
0.1 mmHg; 1H NMR δ 0.94 (t, J ) 7.2, 3H), 1.30-1.55 (m, 4H),
1.85 (br s, 1H), 2.64 (t, J ) 7.2, 2H), 3.79 (s, 2H), 7.25-7.65
(m, 5H); 13C NMR δ 13.8, 20.2, 31.9, 48.9, 53.8, 126.6, 127.8,
128.1, 140.1; MS m/ z 163 (M+, 4), 120 (99), 91 (100), 65 (36).
Rea ction of 3 w ith a n Excess of Bu tyllith iu m .
A
solution of amine 3 (5 mmol, 0.55 g) in Et2O (30 mL) at rt was
treated with BuLi (2.5 M in hexane, 25 mmol, 10 mL)
dropwise. The solution was stirred at rt for 30 min. The
reaction mixture was hydrolyzed with H2O and extracted with
ether. The organic phase was dried and concentrated in vacuo
(15 mmHg), and the resulting crude material was distilled trap
to trap at rt under reduced pressure (0.1 mmHg) to yield 0.6
g (85%) of N-butylpentylamine 10.
Rea ction of 1 w ith Bu tyllith iu m a n d Ben za ld eh yd e.
To a solution of amine 1 (5 mmol, 0.96 g) in Et2O (30 mL) at
rt was added dropwise BuLi (2.5 M in hexane, 25 mmol, 10
mL). The solution was stirred at rt for 30 min. An excess of
PhCHO (30 mmol, 3.18 g) was then added at rt and stirring
was continued for 12 h at the same temperature. The resulting
mixture was hydrolyzed with H2O and extracted with ether.
The organic phase was dried and concentrated in vacuo. From
the resulting crude material 0.57 g (80%) of amine 10 was
obtained by trap to trap distillation (0.1 mmHg). The corre-
sponding residue was purified by flash column chromatogra-
phy (CH2Cl2/THF, 30:1) to give 0.89 g (75%) of diol 17.
1,4-Dip h en yl-2-bu tyn e-1,4-d iol (17): White solid; Rf 0.28
(CH2Cl2/THF, 30:1); 1H NMR δ 4.80-5.20 (broad signal, 2H),
5.45 (s, 2H), 7.25-7.55 (m, 10H); 13C NMR δ 68.7, 85.9, 126.4,
127.8, 128.1, 140.2; MS m/ z 238 (M+, 25), 220 (42), 105 (100),
77 (62).
N,N′-Dibu tyl-5-m eth ylen eh exa h yd r op yr im id in e (19):
Colorless oil; Rf 0.50 (hexane/THF, 5:1); H NMR δ 0.83 (t, J
) 7, 6H), 1.15-1.45 (m, 8H), 2.30 (t, J ) 7.2, 4H), 3.05 (s, 4H),
3.25 (s, 2H), 4.76 (s, 2H); 13C NMR δ 13.8, 20.3, 29.2, 53.6,
58.1, 74.1, 110.2, 139.6; MS m/ z 210 (M+, 17), 209 (100), 98
(30).
1
N,N′-Diben zyl-5-m eth ylen eh exa h yd r op yr im id in e (22):
Colorless oil; Rf 0.41 (hexane/AcOEt, 10:1); 1H NMR δ 3.20 (s,
4H), 3.45 (s, 2H), 3.63 (s, 4H), 4.88 (s, 2H), 7.30 (m, 10H); 13
C
NMR δ 57.7, 57.9, 73.4, 111.0, 126.8, 128.0, 128.9, 138.3, 139.4;
MS m/ z 278 (M+, 25), 277 (100), 91 (92).
Ack n ow led gm en t. This work was supported by the
Direccio´n General de Investigacio´n Cient´ıfica y Te´cnica
(DGICYT, PB92-1005). R. M. Canteli thanks the Mi-
nisterio de Educacio´n y Ciencia for a predoctoral fel-
lowship. Dr. P. Bernad is acknowledged for expert
assistance in mass spectral analysis.
Su p p or tin g In for m a tion Ava ila ble: Analytical data of
12 and copies of 1H and 13C NMR spectra of 3, 10, 11, 13, 17-
19, 21 and 22 (10 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(14) Elderfield, R. C.; Hageman, H. A. J . Org. Chem. 1949, 14, 605.
(15) Bortnick, N.; Luskin, L. S.; Hurwitz, M. D.; Craig, W. E.; Exner,
L. J .; Mirza, J . J . Am. Chem. Soc. 1956, 78, 4039.
J O960025+