Creation of new boron-carbon bonds by dichlorocarbene insertion into the boron-hydrogen bond of amine- and phosphine-boranes

Article abstract of DOI:10.1016/S0040-4020(00)00565-2

A simple approach for constructing a new boron-carbon bond by direct insertion into the B-H bond of amine- and phosphine- borane complexes is described. The outcome of this reaction was studied according to the substituents and the experimental conditions. A preliminary investigation of the reactivity of some insertion products as well as their anti-proliferative activities is also reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00565-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6039±6046
Creation of New Boron±Carbon Bonds by Dichlorocarbene
Insertion into the Boron±Hydrogen Bond of Amine± and
Phosphine±Boranes
a
Laurence Monnier, Jean-Guy Delcros and Bertrand Carboni
b
a,*
a
Synth eÁ se et Electrosynth eÁ se Organiques, UMR CNRS 6510, Universit e de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
b
Groupe de Recherche en Th e rapeutique Anticanc e reuse, CNRS ESA 6027, Facult e de M e decine, 2, Avenue du Professeur L. Bernard, 35043
Rennes Cedex, France
Received 3 April 2000; revised 20 June 2000; accepted 22 June 2000
AbstractÐA simple approach for constructing a new boron±carbon bond by direct insertion into the B±H bond of amine± and phosphine±
borane complexes is described. The outcome of this reaction was studied according to the substituents and the experimental conditions. A
preliminary investigation of the reactivity of some insertion products as well as their anti-proliferative activities is also reported. q 2000
Elsevier Science Ltd. All rights reserved.
Introduction
samarium carbenoids has been used to afford phosphine±
monoalkylborane in good yields. Following our initial
8
For nearly a century, amine± and phosphine±borane
complexes have stimulated research interest from chemists.
However, it is only in the last three decades that a better
understanding of their basic reactions has been the starting
results, we report here a more detailed study of the reactivity
of various amine± and phosphine±borane complexes
toward dichlorocarbene (Scheme 1) and a ®rst investigation
of some aspects of their reactivity and their anti-prolifera-
tive activity.
1
point of new synthetic applications. For example, signi®-
cant advances have been made in the preparation of chiral
non racemic phosphines by using borane both as a protect-
ing and an activating group. Promising results were also
2
Results and Discussion
reported in various other areas, such as boron analogues of
aminoacids and nucleotides, boron-containing host mole-
3
1
2
1a (R ˆPh, RˆH) and 2a (R ˆMe, RˆH) are commercially
available. Phosphine±boranes 1b±1f and amine±boranes
2b and 2c were prepared easily in almost quantitative yields
by exchange reactions of dimethylsul®de by the correspond-
ing amines or phosphines according to the literature (Table
4
5
cules, and in materials sciences. In our laboratory, preli-
minary experiments using triphenylphosphine±borane as
the starting material indicated that dichlorocarbene insertion
into the boron±hydrogen bond should open a new route to
6
1
hitherto unknown borane complexes. The same reaction
was carried out with 1,2-dihydro-1,2-l -azaphosphinine±
1). Addition of sodium cyanoborohydride to phosphine or
3
1
amine hydrohalide afforded 1e (R ˆPh, XˆCN) and 2d
10
procedures ®rst described by Spielvogel et al. Alkylation
2
9
BH and, later by other authors, with dihydro-1H-phos-
3
(R ˆMe, XˆCN). 2e±2f were obtained following the
7
phole-BH3. More recently, methylene insertion with
Scheme 1.
Keywords: carbene; amine±borane; phosphine±borane; insertion; rearrangement; anti-proliferative activity.
*
Corresponding author. Fax: 133-2-99-28-69-78; e-mail: bertrand.carboni@univ-rennes1.fr
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00565-2

6
040
L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
Table 1. Phosphine and amine±boranes 1 and 2
Tritolylphosphine±BH 1b appeared to be slightly more
3
reactive than 1a since total consumption of 1b required
1
a
1b
1c
1d
1e
Ph
1f
1g
approximately 1.5 h at 258C (3b/4bˆ65/35). After 18 h,
4b was the only detected insertion product. Tributylphos-
phine±borane 1c has a similar reactivity, except that the
1
2
R
R
Ph
H
p-Tol
H
n-Bu
H
i-PrO
H
Ph
Cl
Ph
Br
CN
formation of a tri-insertion product (n-Bu) P±B(CHCl )
3
2
Me
H
a
2b
Et
Cl
2c
Et
Br
2d
Me
CN
2e
Me
CO
2f
Me
CO
2 3
R
R
5c was observed after 3 h at 258C (3c/4c/5cˆ31/63/6). 3c
2
H
2
Me
was completely transformed after 18 h (4c/5cˆ28/72). The
insertion reaction proceeded more slowly with (i-PrO) P±
3
BH 1d (30 min, 258C, 1d/3dˆ70/30) and there were only
3
of 2d by triethyloxonium tetra¯uoroborate yielded 2e after
treatment with water. Esteri®cation of 2e with trimethyl-
orthoformate in the presence of boron tri¯uoride etherate
small amounts of a di-insertion product 4d after 90 min at
the same temperature (3d/4dˆ93/7. When the reaction was
carried out at room temperature for 18 h, we obtained a
mixture of mono-, di- and tri-insertion products (3d/4d/
1
1
gave 2f.
5
tuted borane complex Ph P±BH CN 1e has been consumed
dˆ23/65/12). After 5 h at 258C, 80% of the monosubsti-
3
2
Insertion reactions
giving a 7/3 mixture of mono- and di-insertion products. In
contrast, the introduction of a halogen on the boron moiety
resulted in the formation of a single product. Ph P±
Dichlorocarbene was generated according to the Makosza
3
1
2
procedure. Deprotonation of chloroform by means of
sodium hydroxide and a quarternary ammonium salt in a
phase-transfer system affords initially sodium trichloro-
methylide, which dissociates into a dichlorocarbene.
BH(CHCl )Cl 3f or Ph P±BH(CHCl )Br 3g.
3
2
2
The same experiments were then performed on amine±
borane. Me N±BH . 2a was found to be completely trans-
3
3
formed after 15 min at 08C. A mixture of Me N±BH CHCl
2
3
2
First experiments using triphenylphosphine±borane 1a as a
model substrate indicated that the reaction was incomplete
after 30 min at room temperature and revealed the presence
6a and Me N±BH(CHCl ) 7a was obtained together with
3 2 2
an additional compound 9a, whose structure will be
discussed later (6a/7a/9aˆ40/40/20) (Scheme 3).
3
1
1
of a di-insertion product ( P and H NMR, 1a/3a/4aˆ30/
2/8) (Scheme 2). 1a was completely consumed after 15 h
and a ratio 3a/4aˆ90/5 was then measured. Small amounts
6
After 2 h at room temperature, the monoinsertion product
was completely consumed. 7a and the triinsertion complex
8a were the only detected products. When n-butyllithium
and bromotrichloromethane were used to generate dichloro-
carbene, we observed the formation of a major monoinser-
tion product 7a (2a/7a/8a/9aˆ9/61/9/21). Attempt to purify
this crude mixture by distillation resulted in the obtention of
9a without any contaminant in a 40% yield. We then veri-
®ed by heating of the crude reaction mixture at re¯ux of
chloroform that it was the result of the rearrangement of 6a
3
1
of triphenylphosphine (d Pˆ24.9), triphenylphosphine
3
1
oxide (d Pˆ29.8) and another unknown phosphorus
3
1
compound (d Pˆ49.9) were also detected. When the
reaction was performed at 508C for 1 h, a single phos-
phine±borane complex 4a was produced, but large amounts
of Ph P and Ph PO were also observed. The generation of
3
3
dichlorocarbene by addition of n-butyllithium in hexanes to
1
3
a solution of bromotrichloromethane at 21008C only
slightly modi®ed the course of the reaction (1a/3a/4aˆ44/
1
13
11
(Scheme 4). The NMR spectroscopic data, H, C, B,
were in agreement with the proposed structure. This trans-
formation is discussed in the next paragraph.
5
4/2). Sodium trichloracetate was also tested as a source of
1
4
dichlorocarbene with no signi®cant improvement. We
never observed the formation of a tri-insertion product 5a
Ph P±B(CHCl ) .
As described previously for the phosphine complexes, the
addition of dichlorocarbene on monohalogenoborane±
triethylamine complexes only resulted in the formation of
monoinsertion products 6b (RˆCl) and 6c (RˆBr) while,
for the cyanoborane derivative 2d, a small amount of a di-
insertion product was observed after 1 h 30 at room
temperature (6d/7dˆ92/8). With the carbomethoxyborane
3
2 3
Following these preliminary observations, we then turned
our attention to other phosphine±borane complexes 1.
Unless otherwise speci®ed, we chose to generate dichloro-
carbene from chloroform and sodium hydroxide in a phase-
transfer system.
Scheme 2.
Scheme 3.

L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
6041
Scheme 4.
Table 2. Isolated insertion products 3, 4, 6 and 7
Entry
Complex
Yield (%)
Entry
Complex
Yield (%)
3a
4a
4b
3d
3e
4e
3f
Ph
Ph
Tol
3
P±BH
2
CHCl
2
46
25
21
40
24
35
48
3g
7a
6b
6c
6d
6f
Ph
Me
3
P±BHBrCHCl
N±BH(CHCl
N±BHClCHCl
N±BHBrCHCl
2
56
50
65
58
55
45
30
3
P±BH(CHCl
2
)
2
3
2 2
)
3
P±BH(CHCl
P±BH
P±BH(CN)CHCl
P±B(CN)(CHCl
P±BHClCHCl
2
)
2
Et
Et
3
3
2
(i-PrO)
3
2
CHCl
2
2
Ph
3
Ph
3
Ph
3
2
Me
Me
Me
3
3
3
N±BH(CN)CHCl
N±BH(CHCl )(CO
N±B(CHCl (CO Me)
2
2
)
2
2
2
Me)
2
7f
2
)
2
2
complex 2f (RˆCO Me), under the same experimental
tuent on boron prevented a second insertion of the
carbene and allowed the obtention of a single compound.
² Whatever the method used to generate the carbene and
the boron substituents, the amine±boranes complexes are
more reactive than the phosphine±boranes. For a same
2
conditions, the mono-and the di-insertion products were
formed in a 60/40 ratio. They were easily separated by care-
ful distillation.
All these insertion products were air- and moisture-stable
compounds, except 3c±5c and 3d±5d. They were readily
borylated moiety, BH for example, the order of reactiv-
3
ity is the following:
1
characterised by H, B, P NMR, mass spectroscopy and
11
31
1
or) elemental analysis. In particular, the d B were found
1
Me N . Bu P , Ph P , Tol P . ꢀi-PrO† P
3
3
3
3
3
(
in the range 1.6 to 226.3 indicating a signi®cant charge
transfer from the nitrogen or phosphorus to the boron
atom and, therefore, corroborate the presence of a tetracoor-
For a same Lewis base, for example PPh , the boranes
3
can also be classi®ed by increased reactivity.
1
5
dinate boron atom. Isolated insertion products are listed in
Table 2.
BH . BH Cl . BH Br , BH CN
3
2
2
2
The previous results bring the following comments:
Reactivity
²
²
The change in the method of generation of dichlorocar-
bene from phase transfer to a reaction performed in
anhydrous medium starting from BrCCl and n-BuLi
did not cause any major modi®cation. However, the
second method is in general more selective, affording
lower amounts of di-insertion products, probably because
the carbene was present during a shorter time and was not
in excess.
Decomplexation reactions. We envisaged that some of the
previously prepared insertion products could be good
precursors of new hydroborating agents and, for example,
could give access to new dichloromethyl boranes 10
(Scheme 5). The chemistry of such species is extremely
developed, due to the halogen atom a to the boron that
induces an easy intramolecular 1,2 migration in the presence
3
1
6
We never succeeded to stop the reaction after the ®rst
insertion for all amine± and phosphine±BH complexes.
The presence of an halogen (chlorine or bromine) substi-
of a nucleophile (Scheme 5).
3
In order to test this reaction, we ®rst heated unsuccessfully a
Scheme 5.
Scheme 6.

6
042
L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
Scheme 7.
mixture of complex 6a and dec-1-ene. We then decided to
use methyl iodide in excess to generate in situ the free
new compounds were established on the basis of NMR,
mass spectroscopy and elementary analysis (Scheme 8).
1
7
borane. The formation of the phosphonium salt was actu-
ally observed, but, whatever the conditions, no hydrobora-
tion product was obtained. These results were not improved
by using other electrophiles (MeOSO CF , HBF , Et O/
This transformation presumably occurred through an intra-
molecular migration of one hydrogen from boron to the a-
carbon, followed by the addition of the chloride anion
generated in situ to the borylated moiety (Scheme 9).
2
3
4
2
BF ), Thus it seems that, if decomplexation indeed
3
occurred, H BCHCl was too unstable in these conditions
2
2
to hydroborate an alkene (Scheme 6).
Anti-proliferative activity. Previously, a series of
trimethylamine cyanoboranes, trimethylamine carboxybor-
anes, their derivatives, and related compounds were
reported to afford antineoplastic activities. A preliminary
study of the anti-proliferative activity of seven insertion
products (3a, 3e, 3f, 3g, 4e, 6d and 6e) and ®ve starting
complexes (1e, 1f, 1g, 2d and 2f) against murine L1210
leukaemia has been carried out. Among all compounds
tested at concentrations ranging from 0.5 to 50 mM, only
In contrast, if decomplexation did not occur when 9a was
treated with boron trichloride, a new complex 11 was
obtained instead of the expected boron trichloride±
trimethylamine adduct (Scheme 7). The hydrogen atom
carried by the boron atom was replaced by a chlorine
1
9
1
13
11
atom. 11 was characterised by NMR H, C, B and
elementary analysis.
4
e impaired cell growth. An IC50 of 2.9^0.25 mM was
Such redistribution reactions between an amine±borane
complex and a trihalogenoborane, without cleavage of the
boron±nitrogen bond, were already described in the litera-
ture. The formation of dichloroborane was con®rmed by
carrying out the reaction in the presence of hex-1-ene. After
oxidation, hexan-1-ol was recovered in a good yield.
calculated after 2 days of culture with this compound. At
concentrations .5 mM, cells lost viability. Further investi-
gations are required to determine the exact potential of 4e as
an anti-proliferative drug.
1
8
Conclusion
Thermal rearrangement. We described previously the
presence of 9a in the crude mixture besides 6a, when
Me NBH was submitted to the insertion reaction of
dichlorocarbene. Distillation caused the complete conver-
sion of the expected product 6a to 9a. This rearrangement
was the result of an exchange between the hydrogen carried
by boron and one of the chlorine. It could be extended to
other trimethylamine±borane complexes 6d (9 days, re¯ux,
MeOH) and 6f (15 h, re¯ux, MeOH). The structures of these
In summary, we have described the insertion reactions of a
dichlorocarbene into the hydrogen±boron bond of phos-
phine± and amine±borane complexes. Although a second
insertion of the carbene was sometimes dif®cult to prevent,
hitherto unknown organoboranes were isolated successfully
in acceptable to good yields. Preliminary aspects of the
reactivity of these compounds as well as of their anti-prolif-
erative activities were also reported. Further studies are in
3
3
Scheme 8.
Scheme 9.

L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
6043
progress to elucidate the exact mechanism of this inser-
tion reaction and to test other carbenes in order to
synthesise new functionalized amine± and phosphine±
borane complexes.
graphy on silica gel failed. The NMR data were measured
from the spectrum of a 80/20 mixture of 3b/4b
1
(mpˆ1018C). H NMR (CDCl , 300 MHz) d: 2.38 (s, 9H),
3
5.50 (q, J
C NMR (CDCl , 75 MHz) d: 21.5 (s, CH ), 72.0 (CHCl ),
and J ˆ5.3 Hz, 1H), 7.11±7.52 (m, 15H).
H±P
H±H
1
3
3
3
2
1
23.5 (d, JC±Pˆ61.6 Hz, C), 129.7 (d, J ˆ10.6 Hz, CH),
C±P
Experimental
133.4 (d, J ˆ9.8 Hz, CH), 142.1 (d, J ˆ2.3 Hz, CH).
P NMR (CDCl , 121 MHz) d: 8.8. B NMR (CDCl ,
3 3
C±P
C±P
11
3
1
Chloroform was ®rst shaken with conc. H SO , washed with
4
96 MHz) d: 222.3.
2
water, dried with CaCl before ®ltering and distilling. All
2
melting points were determined on a Ko¯er apparatus and
are uncorrected. NMR spectra were measured on a Bruker
AC 200 (200 MHz for H and 50.3 MHz for C) and a
Tritolylphosphine±bis(dichloromethyl)borane 4b. 21%
(after 15 h at r.t. and precipitation with diethylether/heptane
1
13
1
3/1). Mpˆ1578C (dichloromethane). H NMR (CDCl3,
1
13
Bruker AC 300 (300 MHz for H, 75.5 MHz for C,
1
300 MHz) d: 2.41 (s, 9H), 5.70 (dd, J ˆ9.3 Hz, J
H±P
ˆ
3
H±H
3
21 MHz for P and 96 MHz for B). For H and
1
11
1
13
13
C
3.6 Hz, 2H), 7.22±7.61 (m, 15H). C NMR (CDCl ,
NMR, TMS was used as internal standard (dˆ0 ppm) and
75 MHz) d: 21.5 (s, CH ), 70.9 (CH), 121.8 (d, J
3
ˆ
C±P
3
the J values are given in Hz. For P and B NMR, H PO
1
11
3
4
62.2 Hz, C), 129.7 (d, JC±Pˆ11.0 Hz, CH), 134.3 (d,
3
1
(
85%, aq.) and Et OBF were, respectively, used as external
2
JC±Pˆ9.5 Hz, CH), 142.5 (d, J ˆ2.7 Hz, CH). P NMR
C±P
3
1
1
standard. High resolution mass spectra were obtained on a
Varian MAT 311 (Centre R e gional de Mesures Physiques,
Universit e de Rennes 1, France). Elemental analyses were
performed at the Central Laboratory for Analysis, CNRS,
Lyon, (France). Silica gel 60F254 (Merck) was used for
column chromatography.
(CDCl , 121 MHz) d: 8.6. B NMR (CDCl , 96 MHz) d:
3 3
211.8. C H BCl P (447.1): calcd: C, 57.02; H, 4.96;
2
3
24
4
found C, 56.8; H, 5.0.
Tri-(n-butyl)phosphine±dichloromethylborane 3c. All
attempts of puri®cation by distillation or chromato-
graphy on silica gel failed. The NMR data were
measured from the spectrum of a crude mixture of 3c/
General procedure for the insertion of a dichlorocarbene
generated by phase transfer
4c (4/1) after 30 min at r.t. Other phosphorus deriva-
1
tives without a borane moiety were also present.
NMR ([d
9H); 1.10±1.85 (m, 18H); 5.78 (dt, JH±Pˆ22.7 Hz,
H
To a solution of 10 mmol of a phosphine± or amine±borane
complex in 70 ml of CHCl were added 500 ml of triethyl-
8
]-toluene, 300 MHz) d: 0.81 (t, JH±Hˆ7.2 Hz,
3
1
3
benzylammonium chloride and 32 g of a 50% aqueous solu-
tion of sodium hydroxide (40 equiv.). The mixture was
stirred mechanically very vigorously for the time and at
the temperature, which were given below for each complex.
The organic layer was washed with water (2£10 ml), dried
J
H±Hˆ4.0 Hz, 1H). C NMR ([d
13.7 (s, CH
CH
); 24.7 (d, JC±Pˆ2.4 Hz, CH
NMR ([d
8
]-toluene, 75 MHz) d:
); 21.1 (d, JC±Pˆ34.2 Hz, CH
); 24.5 (s,
P
3
2
3
1
); 73.5 (CH).
2
2
1
1
-toluene, 121 MHz) d: 6.6. B NMR ([d
]-
8
8
toluene, 96 MHz) d: 224.1 (dt, JB±Pˆ61.2 Hz, JB±H
ˆ
(
MgSO ) and ®ltered. The ®ltrate was concentrated under
82.1 Hz).
4
reduced pressure. The residue was puri®ed by recrystalliza-
tion or bulb to bulb distillation.
Tri-(n-butyl)phosphine±bis(dichloromethyl)borane 4c.
All attempts of puri®cation by distillation or chroma-
tography on silica gel failed. The NMR data were measured
from the spectrum of a crude mixture of 3c/4c/5c (31/63/6)
Triphenylphosphine±(dichloromethyl)borane 3a. 46%
(
after 15 h at r.t. and precipitation with diethylether).
H
1
Mpˆ1348C (dichloromethane).
NMR (CDCl3,
after 3 h at r.t. Other phosphorus derivatives without a
borane moiety were also present. H NMR ([d ]-toluene,
1
3
7
00 MHz) d: 5.52 (q, J ˆ5.9 and J ˆ5.3 Hz, 1H),
8
H±P
H±H
1
.26±7.71 (m, 15H). C NMR (CDCl , 75 MHz) d: 71.9
3
300 MHz) d: 0.81 (t, JH±Hˆ7.2 Hz, 9H); 1.10±1.85 (m,
3
1
3
(
CH), 126.6 (d, JC±Pˆ59.0 Hz, C), 129.0 (d, J ˆ10.9 Hz,
18H); 6.06 (dd, JH±Pˆ19.2 Hz, JH±Hˆ4.0 Hz, 2H).
NMR ([d ]-toluene, 75 MHz) d: 13.7 (s, CH ); 20.5 (d,
); 24.6 (s, CH
); 24.8 (d, JC±Pˆ3.7 Hz,
]-toluene, 121 MHz) d: 1.8.
]-toluene, 96 MHz) d: 213.5 (dd, JB±Pˆ73.8,
C
C±P
CH), 131.8 (d, J ˆ2.1 Hz, CH), 133.6 (d, J ˆ9.6 Hz,
C±P
11
CH). P NMR (CDCl , 121 MHz) d: 10.8. B NMR
8
3
C±P
3
1
J
C±Pˆ34.2 Hz, CH
3
2
2
3
1
(
C, 63.56; H, 5.01; found C, 63.4; H, 5.1.
CDCl , 96 MHz) d: 222.3. C H BCl P (359.0): calcd
2
CH
2
); 72.9 (CH). P NMR ([d
8
3
19 18
1
1
B NMR ([d
8
JB±Hˆ67.2 Hz).
Triphenylphosphine±bis(dichloromethyl)borane
2
4a.
5% (after 1 h at 508C and precipitation with diethylether).
Tri-(n-butyl)phosphine±tris(dichloromethyl)-borane 5c.
All attempts of puri®cation by distillation or chroma-
tography on silica gel failed. The NMR data were measured
from the spectrum of a crude mixture of 4c/5c (28/72) after
1
Mpˆ1168C (dichloromethane).
H
NMR (CDCl3,
3
00 MHz) d: 5.73 (dd, J ˆ9.7 Hz, J ˆ3.7 Hz, 2H),
H±P
H±H
1
.31±7.72 (m, 15H). C NMR (CDCl , 75 MHz) d: 66.0
3
7
3
(
CH), 124.9 (d, JC±Pˆ59.8 Hz, C), 129.0 (d, J ˆ10.9 Hz,
15 h at r.t. Other phosphorus derivatives without a borane
moiety were also present. H NMR ([d ]-toluene, 300 MHz)
C±P
1
CH), 132.1 (d, J ˆ3.2 Hz, CH), 133.6 (d, J ˆ9.6 Hz,
8
C±P
C±P
3
1
CH). P NMR (CDCl , 121 MHz) d: 9.9. B NMR (CDCl ,
11
d: 0.76 (t, JH±Hˆ7.2 Hz, 9H); 1.10±1.85 (m, 18H); 6.03 (d,
J
8
3
3
1
3
9
4
6 MHz) d: 211.4. C H BCl P (441.9): calcd C, 54.35; H,
4
H±Hˆ10.5 Hz, 3H. C NMR ([d
]-toluene, 75 MHz) d:
); 24.5 (s, CH );
2
0
18
.11; found C, 54.3; H, 4.1.
13.5 (s, CH
2
3
); 20.8 (d, JC±Pˆ31.7 Hz, CH
2
2
3
1
5.7 (d, JC±Pˆ6.1 Hz, CH ); 71.5 (CH). P NMR ([d ]-tolu-
2
8
1
1
Tritolylphosphine±(dichloromethyl)borane 3b. All
attempts of puri®cation by recrystallization or chromato-
ene, 121 MHz) d: 0.9. B NMR ([d
29.3 (d, JB±Pˆ70.2 Hz).
8
]-toluene, 96 MHz) d:

6
044
L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
Triisopropylphosphite±(dichloromethyl)borane 3d. 40%
(
Triphenylphosphine±(dichloromethyl)bromoborane 3g.
56% (after 15 h at r.t. and precipitation with diethylether).
after 30 min at r.t. and distillation). Bp0.01 mmHgˆ70±758C.
1
1
H NMR (CDCl , 300 MHz) d: 1.33 (d, JH±Hˆ6.2 Hz, 18H),
Mpˆ1728C (dichloromethane).
H
NMR (CDCl3,
3
1
.75 (br q, JH±Bˆ90.0 Hz, 2H), 4.72 (d sept, J ˆ6.2 Hz,
300 MHz) d: 4.36 (m, 1H), 5.48 (t, J
and JH±Pˆ3.7 Hz,
1H), 7.35±7.80 (m, 15H). C NMR (CDCl , 75 MHz) d:
3
H±H
H±H
1
3
JH±Pˆ1.8 Hz, 3H), 5.62 (dt, J ˆ11.2 Hz, J ˆ4.9 Hz,
H±P
H±H
1
3
1
H). C NMR (CDCl , 75 MHz) d: 23.9 (d, J ˆ3.8 Hz,
69.0 (CH), 124.4 (d, JC±Pˆ63.5 Hz, C), 129.2 (d, J
31
ˆ
3
C±P
C±P
3
1
CH ), 72.2 (d, J ˆ6.3 Hz, CH). P NMR (CDCl ,
10.7 Hz, CH), 132.4 (d, J ˆ2.3 Hz, CH), 134.1 (d,
3
C±P
3
C±P
1
1
1
9
21 MHz) d: 89.1 (q, J ˆ113.0 Hz). B NMR (CDCl3,
P±B
J
ˆ8.9 Hz, CH). P NMR (CDCl , 121 MHz) d: 1.5.
C±P
3
1
1
6 MHz) d: 226.2 (dt, JP±Bˆ120.1 Hz, JB±Hˆ98.8 Hz).
B NMR (CDCl , 96 MHz) d: 211.5. C H BBrCl P
3 19 17 2
(
437.9): calcd C, 52.11; H, 3.91; found C, 52.0; H, 4.0.
Triisopropylphosphite±bis(dichloromethyl)borane 4d.
The NMR data were measured from the spectrum of a 25/
Trimethylamine±(dichloromethyl)borane 6a. The NMR
data were measured from the spectra of the crude mixture of
65/12 mixture of 3d/4d/5d obtained after 18 h at r.t. and the
spectrum of pure 3d. H NMR (CDCl , 300 MHz) d: 1.40 (d,
1
1
6a, 7a and 9a (4/4/2) obtained after 15 min at 08C. H
3
JH±Hˆ6.2 Hz, 18H), 4.88 (d sept, J ˆ6.2 Hz, J
ˆ
NMR (CDCl , 200 MHz) d: 2.74 (s, 9H), 5.59 (t, J
H±H
4.2 Hz, 1H). C NMR (CDCl , 50 MHz) d: 52.8 (CH ), 70.0
3 3
(CH).
ˆ
H±H
H±P
3
1
3
0
.9 Hz, 3H), 5.67 (dd, J ˆ17.6 Hz, J ˆ4.1 Hz, 2H.
H±P
H±H
1
3
C NMR (CDCl , 75 MHz) d: 23.9 (d, J ˆ4.1 Hz,
3
C±P
3
1
CH ), 70.0 (CH), 73.8 (d, J ˆ8.9 Hz, CH). P NMR
3
C±P
1
1
(
(
9
CDCl , 121 MHz) d: 75.5 (q, JP±Bˆ133.4 Hz). B NMR
Trimethylamine±bis(dichloromethyl)borane 7a. 50%
(after 1 h at r.t. and precipitation with diethylether).
3
CDCl3, 96 MHz) d: 214;2 (dd, J ˆ140.4, JB±Hˆ
P±B
1
9.7 Hz).
Mpˆ918C. H NMR (CDCl , 300 MHz) d: 3.00 (s, 9H),
3
1
3
5
53.2 (CH ), 70.0 (CH). B NMR (CDCl , 96 MHz) d: 21.1
.80 (d, J ˆ2.3 Hz, 2H,). C NMR (CDCl , 75 MHz):
H±H
3
1
3 3
1
Trisopropylphosphite±tris(dichloromethyl)borane 5d.
As for 4d, the NMR data were measured from the spectrum
of a 23/65/12 mixture of 3d/4d/5d and the spectrum of pure
(d, JB±Hˆ110.0). C H BCl N (238.8): calcd C, 25.15; H,
5
12
4
5.06; found C, 25.7; H, 5.1.
1
3
1
d. H NMR (CDCl , 300 MHz) d: 1.45 (d, J ˆ6.2 Hz,
3
H±H
8H), 4.98 (d sept, J ˆ6.2 Hz, J ˆ0.9 Hz, 3H), 5.89 (d,
Trimethylamine±tris(dichloromethyl)-borane 8a. The
NMR data were measured from the spectra of the crude
H±H
H±P
1
3
JH±Pˆ13.8 Hz, 3H). C NMR (CDCl , 75 MHz) d: 23.6 (d,
3
3
1
1
mixture 7a and 8a (8/2) obtained after 2 h at r.t. H NMR
JC±Pˆ4.9 Hz, CH ), 75.5 (d, J ˆ10.6 Hz, CH). P NMR
3
C±P
1
1
13
(CDCl , 200 MHz) d: 3.24 (s, 9H), 5.97 (s, 3H). C NMR
(
(
CDCl , 121 MHz) d: 65.4 (q, J ˆ93.5 Hz). B NMR
3
P±B
3
1
(CDCl , 50 MHz): 53.5 (CH ): 70.0 (CH). B NMR
1
CDCl , 96 MHz) d: 28.8 (d, J ˆ152.8 Hz).
3
P±B
3
3
(
CDCl , 96 MHz) d: 24.0.
3
Triphenylphosphine±(dichloromethyl)cyanoborane 3e.
4% (after 15 h at r.t. and precipitation with diethylether).
2
Triethylamine±(dichloromethyl)chloroborane 6b. 65%
(after 1.5 h at r.t.). Oil which decomposed during the distil-
1
Mpˆ1728C (dichloromethane).
H
NMR (CDCl3,
1
2
7
1
1
00 MHz) d: 5.28 (dd, J
and JH±Pˆ3.6 Hz, 1H), 7.30±
lation. H NMR (CDCl , 200 MHz) d: 1.30 (t, Jˆ7.3 Hz,
H±H
3
1
.78 (m, 15H). C NMR (CDCl , 50 MHz) d: 66.6 (CH),
3
13
9H), 3.20 (m, 6H), 5.59 (d, J ˆ2.4 Hz, 1H). C NMR
H±H
3
1
1
23.6 (d, JC±Pˆ64.5 Hz, C), 129.5 (d, J ˆ11.1 Hz, CH),
11
P NMR (CDCl , 121 MHz) d: 5.4. B NMR (CDCl ,
(CDCl , 50 MHz): 9.7 (CH ), 51.2 (CH ): 71.1 (CH).
3
B
C±P
3
2
32.8 (d, JC±Pˆ2.7 Hz, CH), 133.7 (d, J ˆ9.1 Hz, CH).
C±P
NMR (CDCl , 96 MHz) d: 1.6 (d, JB±Hˆ124.5 Hz).
3
3
1
3
3
9
6 MHz) d: 222.7 (dd, JB±Pˆ76.1 Hz, JB±Hˆ67.3 Hz).
Triethylamine±(dichloromethyl)bromoborane 6c. 58%
after 15 h at r.t.). Oil which decomposed during the distil-
(
1
Triphenylphosphine±bis(dichloromethyl)cyanoborane
e. 35% (after 24 h at r.t. and precipitation with diethyl-
lation. H NMR (CDCl , 200 MHz) d: 1.32 (t, J ˆ7.3 Hz,
3
H±H
1
3
4
9H), 3.28 (m, 6H), 5.64 (d, JH±Hˆ2.4 Hz, 1H). C NMR
1
11
ether). Mpˆ1588C (dichloromethane). H NMR (CDCl ,
(CDCl , 50 MHz): 9.6 (CH ), 51.7 (CH ), 69.0 (CH).
3
B
3
3
2
CDCl , 200 MHz) d: 5.57 (d, J ˆ8.4 Hz, 2H), 7.31±
NMR (CDCl , 96 MHz) d: 0.4 (d, JB±Hˆ121.4 Hz).
3
H±P
3
1
3
7
1
1
.87 (m, 15H). C NMR (CDCl 50 MHz) d: 66.6 (CH),
3,
22.7 (d, JC±Pˆ62.9 Hz, C), 129.5 (d, J ˆ11.1 Hz, CH),
Trimethylamine±(dichloromethyl)cyanoborane 6d. 55%
(after 15 h at r.t. and precipitation with diethylether).
C±P
33.0 (d, JC±Pˆ2.5 Hz, CH), 134.6 (d, J ˆ9.5 Hz, CH.
C±P
3
1
11
P NMR (CDCl , 121 MHz) d: 7.2. B NMR (CDCl
1
Mpˆ1268C (sublimation). H NMR (CDCl , 300 MHz) d:
3
3,
3
1
3
9
6 MHz) d: 213.0 (d, JP±Bˆ65.0 Hz). C H BCl NP
2.28 (m, 1H), 2.88 (s, 9H), 5.49 (d, J ˆ2.7 Hz, 1H).
NMR (CDCl , 75 MHz): 52.3 (CH ), 63.0 (CH), 129.0 (C).
3 3
B NMR (CDCl , 96 MHz) d: 28.0 (d, J ˆ110.0 Hz).
C H BCl N (180.9): calcd C, 33.20; H, 6.13; found C,
5 11 2 2
C
21
17
4
H±H
(
467.0): calcd C, 54.01; H, 3.67; found C, 54.2; H, 3.9.
1
1
3
B±H
Triphenylphosphine±(dichloromethyl)chloroborane 3f.
8% (after 15 h at r.t. and precipitation with diethylether).
4
33.5; H 6.0.
1
H
Mpˆ1878C (dichloromethane).
NMR (CDCl3,
3
7
1
1
00 MHz) d: 5.44 (t, J
and JH±Pˆ3.3 Hz, 1H), 7.29±
Trimethylamine±(dichloromethyl)carbomethoxyborane
6f. 45% (after 2 h at r.t. and distillation). Bp
H±H
1
.78 (m, 15H). C NMR (CDCl , 75 MHz) d: 70.1 (CH),
3
ˆ558C.
3
0.05 mmHg
1
24.4 (d, JC±Pˆ61.8 Hz, C), 129.1 (d, J ˆ10.9 Hz, CH),
Mpˆ718C. H NMR (CDCl , 300 MHz) d: 2.36 (m, 1H),
C±P
3
1
3
32.3 (d, JC±Pˆ2.3 Hz, CH), 134.0 (d, J ˆ9.1 Hz, CH).
C±P
2.95 (s, 9H), 3.59 (s, 3H), 5.87 (d, J ˆ2.2 Hz, 1H).
NMR (CDCl , 75 MHz): 48.7 (CH ), 52.5 (CH ), 65.0 (CH).
3 3 3
C
H±H
3
1
11
P NMR (CDCl , 121 MHz) d: 1.7. B NMR (CDCl ,
3
3
1
1
96 MHz) d: 27.8. C H BCl P (393.5): calcd C, 58.00;
H, 4.35; found C, 58.2; H, 4.5.
B NMR (CDCl , 96 MHz) d: 24.5 (d, J ˆ103.4 Hz). IR
1
9
17
3
3
B±H
2
1
(nujol):nˆ2405 cm (B±H); 1650 (CO). C H BCl NO
6 14 2 2

L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
6045
2
1
(
6
213.9): calcd C, 33.69; H, 6.60; N, 6.55; found C, 33.6; H
.4; N 6.6.
(KBr):nˆ1687 cm (CO). C H BCl NO (213.9): calcd
6
14
2
2
C, 33.69; H, 6.60; N, 6.55; found C, 33.8; H, 6.5; N, 6.5.
Trimethylamine±bis(dichloromethyl)carbomethoxybor-
ane 7f. 30% (the residue obtained after distillation of 6e was
Anti-proliferative activity
1
puri®ed by sublimation). Mpˆ998C. H NMR (CDCl ,
3
Murine L1210 leukaemia cells were cultured in RPMI 1640
(Eurobio, Les Ulis, France) supplemented with 10% heat-
inactivated foetal calf serum (Boehringer Mannheim,
1
3
300 MHz) d: 3.20 (s, 9H), 3.62 (s, 3H), 5.95 (s, 2H).
NMR (CDCl , 75 MHz): 49.5 (CH ), 53.0 (CH ), 69.0 (CH).
C
3
3
3
1
1
B NMR (CDCl , 96 MHz) d: 24.8. C H BCl NO
3
7
14
4
2
Mannheim, germany), 2 mM l-glutamine, penicillin
100 U/ml) and streptomycin (50 mg/ml) (Biomerieux,
Â
(
296.8): C, 28.33; H, 4.75; found C, 28.6; H, 4.6.
(
Marcy l'Etoile, France). Cell growth was monitored in 96
well-plates by determination of formazan formation from
Redistribution reaction of 9a with boron trichloride
.64 mmol of BCl (3.43 M in hexane, 186 ml) was added
3
-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bro-
0
mide (Sigma Chemical Co., St Louis, MO, USA)
(Mosmann, 1983).
3
dropwise to a solution of 9a (100 ml, 0.64 mmol) and 79 ml
0.64 mmol) of hex-1-ene in 0.5 ml of hexane at 2788C.
After stirring for 15 min, the precipitate 11 was ®ltered.
(
Cells were seeded in 100 ml culture medium at a density of
2.5 104 cells/ml in presence of 10 ml of various concentra-
tions of the drug to be tested. Ten millimolar stock solution
of the various drugs were made in DMSO. Stock solutions
were diluted in culture medium. Final concentration of
DMSO did not overreach 0.2%, concentration above
which DMSO exerts a cytotoxic effect. After 48 h of culture,
10 ml of an MTT solution at 5 mg/ml were added to each
well. The plates were centrifuged 5 min at 1000 rpm after
4 h incubation. Supernatant was removed and formazan
crystals were dissolved in 150 ml DMSO. Absorbance
measurements were performed on a Titertek Multiskan
microreader.
1
mˆ72 ml. 60%. Mpˆ1118C. H NMR (CDCl , 200 MHz)
3
1
d: 2.97 (s, 9H), 3.15 (s, 2H). C NMR (CDCl , 50 MHz):
3
3
1
1
37.4 (CH ), 50.4 (CH ). B NMR (CDCl , 96 MHz): d: 8.5.
C H BCl N (190.3): C, 25.25; H 5.83; N, 7.36; found C,
2 3 3
4
11
3
25.4; H, 5.8; N, 7.3.
Thermal rearrangement of 6
Trimethylamine±(chloromethyl)chloroborane 9a. To a
solution of 7.4 mmol (730 ml) of bromotrichloromethane
in 20 ml of THF cooled at 21008C was added dropwise
4
1
.9 ml of n-BuLi (1.5 M in hexanes, 7.4 mmol). After
0 min, a solution of 500 ml of 2a (6.76 mmol) in 50 ml
of THF was added dropwise for 1 h. The mixture was
kept one hour more at 21008C and was then allowed to
warm slowly up to r.t. before the THF was evaporated
under reduced pressure. The residue was treated with 5 ml
of brine, extracted with methylene chloride (3£10 ml) and
Acknowledgements
We thank S. Dagorne for her technical assistance.
dried (MgSO ). Evaporation of the solvent yielded a resi-
4
due, which was puri®ed by bulb to bulb distillation.
References
1
mˆ424 ml. 40%. Bp
ˆ80±858C. H NMR (CDCl ,
0
.05 mmHg
3
3
3
7
9
00 MHz) d: 2.78 (s, 9H), 2.97 (dd, Jˆ2.3 and 13.5 Hz, 1H),
1. Monnier, L.; Carboni, B. Tetrahedron 1999, 55, 1197±1248.
2. Ohff, M.; Holz, J.; Quirmbach, M.; B oÈ rner, A. Synthesis 1998,
1391, 1415.
1
3
.18 (dd, Jˆ2.3 and 13.5 Hz, 1H). C NMR (CDCl ,
3
1
1
5 MHz): 37.3 (CH ), 50.4 (CH ). B NMR (CDCl3,
2
3
6 MHz): 2.9.
3. Morin, C. Tetrahedron 1994, 50, 12521±12569. (b) Spielvogel,
B. F.; Phosphorus, Sulfur Silicon 1994, 87, 267±276. (c) Soloway,
A. H.; Zhuo, J. C.; Rong, F. G. A.; Lunato, J.; Ives, D. H.; Barth, R.
F.; Anisuzzamanan, A. K. M.; Barth, C. D.; Barnum, B. A.
J. Organomet. Chem. 1999, 581, 150±155.
4. (a) Worm, K.; Schmidtchen, F. P.; Schier, A.; Sch aÈ fer, A.;
Hesse, M. Angew. Chem. Int. Ed. Engl. 1994, 33, 327±329.
(b) Bien, J. T.; Eschner, M. J.; Smith, B. J. Org. Chem. 1995,
60, 4525±4529. (c) Nozaki, K.; Yoshida, M.; Takaya, H. Angew.
Chem. Int. Ed. Engl. 1994, 33, 2452±2454. (d) Nozaki, K.; Tsut-
sumi, T.; Takaya, H. J. Org. Chem. 1995, 60, 6668±6669.
(e) Nozaki, K.; Yoshida, M.; Takaya, H. Bull. Chem. Soc. Jpn
1996, 69, 2043±2052.
Trimethylamine±(chloromethyl)chlorocyanoborane 9d.
A solution of 80 ml (0.44 mmol) of Me NBH(CN)(CHCl )
3
2
6d in 6 ml of methanol and 2 ml of water was heated at
re¯ux for 9 days. After extraction with chloroform
(
(
3£5 ml), the combined organic layers were dried
MgSO ) and concentrated. The residue was puri®ed by
4
column chromatography on silica gel [R ˆ0.6 (dichloro-
f
1
methane)]. 70%. Mpˆ1368C. H NMR (CDCl , 300 MHz)
3
d: 2.95 (s, 9H); 2.97 (d, Jˆ14.4 Hz, 1H), 3.09 (d,
1
3
Jˆ14.4 Hz, 1H). C NMR (CDCl , 75 MHz): 35.9 (CH ),
3
2
1
1
5
0.4 (CH ). B NMR (CDCl , 96 MHz): 22.3.
3 3
5
. (a) Paine, R. T.; Narula, C. K. Chem. Rev. 1990, 90, 73±91.
Trimethylamine±(chloromethyl)chlorocarbomethoxy-
borane 9f. 9f was obtained from 6f after 15 h of re¯ux
according to the same experimental procedure as for 9d.
(b) Baldus, H. P.; Jansen, M. Angew. Chem. Int. Ed. Engl. 1997, 36,
328±343. (c) Parry, R. J. Chem. Ed. 1997, 74, 512±518.
(d) Goto, Y.; Sasaki, M.; Hashizume, M.; Suzuki, M. J. Eur.
Ceram. Soc. 1999, 19, 2695±2700.
1
R ˆ0.2 (heptane/ether: 1/1). 60%. Mpˆ1348C. H NMR
f
(
1
(
2
CDCl , 300 MHz) d: 3.00 (s, 9H), 3.04 (d, Jˆ13.9 Hz,
6. Bedel, C.; Foucaud, A. Tetrahedron Lett. 1993, 34, 311±314.
Â
7. Keglevich, G.; Ujsz a szy, K.; Sz oÈ ll oà sy, A.; Lud a nyi, K.; T oÄ ke,
3
1
3
H), 3.28 (d, Jˆ13.8 Hz, 1H), 3.64 (s, 3H). C NMR
CDCl , 75 MHz): 36.5 (CH ), 49.4 (CH ), 50.6 (CH ),
3
L. J. Organomet. Chem. 1996, 516, 139±145.
8. Imamoto, T.; Yamanoi, Y. Chem. Lett. 1996, 705±706.
2
3
3
1
1
07.0 (CO).
B NMR (CDCl , 96 MHz): 0.0. IR
3

6
046
L. Monnier et al. / Tetrahedron 56 (2000) 6039±6046
Progress; Diehl, P., Fluck, E., Kosfeld, R., Eds.; Springer: Berlin,
9
1
1
. Wisian-Neilson, P.; Das, M. K.; Spielvogel, B. Inorg. Chem.
978, 17, 2327±2329.
0. Spielvogel, B. F. Advances in Boron and the Boranes; Lieb-
1978.
16. Matteson, D. S. Stereodirected Synthesis with Organoboranes,
Springer: Berlin, 1995.
man, J. F., Greenberg, R. E., Eds.; VCH: New York, 1988 (p 329).
1
3
1
1
5
1
1. Mittakanti, M.; Feakes, D. A.; Morse, K. W. Synthesis 1992,
80±382.
17. For a similar approach with Ph PBH , see: Pelter, A.;
3
3
Rosser, R.; Mills, S. J. Chem. Soc., Chem. Commun. 1981,
2. Makosza, M. Pure Appl. Chem. 1975, 43, 439±462.
3. Miler, W. T.; Kim, C. S. Y. J. Am. Chem. Soc. 1959, 81, 5008±
009.
1
1
1
014±1015.
8. Ref. 1, p 1209.
9. Spielvogel, B. F.; Sood, A.; Shaw, B. R.; Hall, I. H. Current
4. Wagner, W. M.; Kloosterziel, H.; Van Der Ven, S. Recl. Trav.
Topics in the Chemistry of Boron; Kabalka, G. W., Ed.; Royal
Society of Chemistry: Cambridge, 1994 (p 193).
Chim. Pays-Bas 1961, 80, 740±746.
5. N oÈ th, H.; Wrackmeyer, B. NMR Basic Principles and
1