Reactions of the bornyl and fenchyl grignard reagent with chlorophosphanes - Diastereoselectivity and mechanistic implications

Article abstract of DOI:10.1002/ejoc.200900908

The reactions of the bornyl and fenchyl Grignard reagent with the chlorophosphanes Ph₂PCl, PCl₃ and (Et₂N) ₂PCl, respectively, were studied by multinuclear NMR spectroscopy. The diastereoselectivity was found to be independent of the diastereomeric composition of the bornyl and fenchyl Grignard reagent (e.g., the endo/exo ratio), but dependent on the chlorophosphanes used. The results are consistent with a reaction mechanism that involves SET processes and radical intermediates. No or little diastereoselectivity was observed for the reactions involving Ph₂PCl and PCl₃. The reactions of the bornyl and fenchyl Grignard rea-gent with (Et₂N)₂PCl provided bornylP(NEt₂)₂ (4a) and βfenchylP(NEt ₂)₂ (10b) with high diastereoselectivity (of 92% and 88% de). The novel chiral phosphane oxides bornylPh₂PO (2a), isobornylPh₂PO (2b), a-fenchylPh₂PO (8a) and β-fenchylPh₂PO (8b), phosphinic acids bornylP(O)(H)(OH) (5a) and β-fenchylP(O)(H)(OH) (11b) and phosphonic acids bornylP(O)(OH)₂ (6a) and β-fenchylP(O)(OH)₂ (12b) were isolated as colorless crystals. The molecular structures of 2b, 8a, 8b, 6a and 12b were determined by X-ray crystallography.

Full text of DOI:10.1002/ejoc.200900908

FULL PAPER
DOI: 10.1002/ejoc.200900908
Reactions of the Bornyl and Fenchyl Grignard Reagent with
Chlorophosphanes – Diastereoselectivity and Mechanistic Implications
Jens Beckmann*[a] and Alexandra Schütrumpf[a]
Keywords: Grignard reaction / Nucleophilic substitution / Radical reactions
The reactions of the bornyl and fenchyl Grignard reagent
with the chlorophosphanes Ph2PCl, PCl3 and (Et2N)2PCl,
respectively, were studied by multinuclear NMR spec-
troscopy. The diastereoselectivity was found to be indepen-
dent of the diastereomeric composition of the bornyl and
gent with (Et2N)2PCl provided bornylP(NEt2)2 (4a) and β-
fenchylP(NEt2)2 (10b) with high diastereoselectivity (of 92%
and 88% de). The novel chiral phosphane oxides born-
ylPh2PO (2a), isobornylPh2PO (2b), α-fenchylPh2PO (8a) and
β-fenchylPh2PO (8b), phosphinic acids bornylP(O)(H)-
fenchyl Grignard reagent (e.g., the endo/exo ratio), but de- (OH) (5a) and β-fenchylP(O)(H)(OH) (11b) and phosphonic
pendent on the chlorophosphanes used. The results are con-
sistent with a reaction mechanism that involves SET pro-
cesses and radical intermediates. No or little diastereoselec-
tivity was observed for the reactions involving Ph2PCl and
PCl3. The reactions of the bornyl and fenchyl Grignard rea-
acids bornylP(O)(OH)2 (6a) and β-fenchylP(O)(OH)2 (12b)
were isolated as colorless crystals. The molecular structures
of 2b, 8a, 8b, 6a and 12b were determined by X-ray crystal-
lography.
can be auspiciously changed to 96:4 by thermal epimeri-
zation (refluxing toluene, 12 h). The closely related fenchyl
Grignard comprises α-fenchylmagnesium chloride and β-
fenchylmagnesium chloride in with an endo/exo ratio of
80:20, which can be entirely inverted to 20:80 by thermal
epimerization. The diastereomeric composition of the Grig-
nard reagents was unambiguously determined by reaction
with the soft model electrophile triphenyltin chloride giving
rise the formation of air-stable diastereomeric mixtures of
terpenoid alkyltriphenylstannanes that were qualitatively
and quantitatively assessed by 119Sn, 13C and 1H NMR
spectroscopy.[4]
We have now studied the reaction of the (epimerized)
bornyl and fenchyl Grignard reagents with the selected
chlorophosphanes, Ph2PCl, PCl3 and (Et2N)2PCl. These re-
actions provided diastereomeric mixtures of bornylphos-
phanes and isobornylphosphanes as well as α-fenchylphos-
phanes and β-fenchylphosphanes. Surprisingly, the dia-
stereoselectivity of these reactions is completely indepen-
dent of the initial endo/exo ratio of the Grignard reagents,
but depends on the chlorophosphanes used.
Introduction
The preparation of Grignard reagents by the direct reac-
tion of Mg with alkyl halides proceeds via single-electron
transfer (SET) and involves alkyl radical intermediates.
Consequently, this method furnishes racemic Grignard rea-
gents even if optically active alkyl halides with α-carbon
atoms as sole chiral centers are used.[1] As a result, the prep-
aration of enantiomerically enriched Grignard reagents
with α-carbon atoms being the sole chiral centers requires
alternative routes, which are rather tedious and somewhat
limit the synthetic utility.[2] We turned our attention to dia-
stereomeric Grignard reagents prepared by the direct
method from Mg and sec-alkyl chlorides derived from natu-
rally occurring inexpensive monoterpenes, such as men-
thol,[3] borneol and fenchol.[4] These Grignard reagents
have three chiral centers and consist of configurationally
stable mixtures of diastereomers, which differ only in the
configuration of the α-carbon atom. Consistent with the
SET mechanism, the ratio of the diastereomers is entirely
independent of the initial configuration of the α-carbon
atom of the alkyl chloride. The menthyl Grignard reagent
contains equal amounts of menthylmagnesium chloride and
neomenthylmagnesium chloride.[3] The bornyl Grignard
reagent contains bornylmagnesium chloride and isobornyl-
magnesium chloride with an endo/exo ratio of 67:33, which
Results and Discussion
The stoichiometric reactions of the (epimerized) bornyl
and fenchyl Grignard reagents with the chlorophosphanes,
Ph2PCl, PCl3 and (Et2N)2PCl, respectively, provided dia-
stereomeric mixtures of bornylphosphanes and isobornyl-
phosphanes (1–6) as well as α-fenchylphosphanes and β-
fenchylphosphanes (7–12), which were quantitatively and
qualitatively assessed by 1D and 2D 31P-, 31C- and 1H
[a] Institut für Chemie und Biochemie, Anorganische und Analyti-
sche Chemie, Freie Universität Berlin,
Fabeckstr. 34–36, 14195 Berlin, Germany
E-mail: beckmann@chemie.fu-berlin.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900908.
Eur. J. Org. Chem. 2010, 363–369
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Beckmann, A. Schütrumpf
FULL PAPER
NMR spectroscopy (see Schemes 1 and 2). The assignment
The crude yield of 1a/1b and 7a/7b was 58% and 48%,
of the endo and exo configurations was supported by com- respectively.[6] Attempts to purify these mixtures by col-
3
parison of indicative J(31P-CC-13C) couplings with those umn chromatography lead to partial oxidation to phos-
of endo- and exo-norbornyldimethylphosphane oxide based phane oxides. Therefore, the crude mixtures were treated
on the Karplus relation.[5] The diastereoselectivity varied with H2O2 and converted into the alkyldiphenylphosphane
dramatically for the chlorophosphanes used and was deter- oxides bornylPh2PO (2a) and isobornylPh2PO (2b) as well
mined from the crude reaction mixtures by integration of as α-fenchylPh2PO (8a) and β-fenchylPh2PO (8b), which
the two well-separated 31P-NMR chemical shifts of the endo were separated by column chromatography. Compounds
and exo diastereomers. Surprisingly, the diastereoselectivity 2a, 2b, 8a and 8b were isolated pure as colorless crystals
was found to be completely independent of the initial in yields of 14%, 15%, 20% and 9%, respectively. The mo-
endo/exo ratio of the Grignard reagents.
lecular structures of 2b, 8a and 8b are shown in Figures 1,
The reaction of the bornyl and fenchyl Grignard reagent 2, and 3 and independently confirm the absolute (Flack
with Ph2PCl proceeds with no and very little diastereoselec- parameter) and relative (endo or exo) configuration of the
tivity and produced mixtures of alkyldiphenylposphanes terpenoid residues. The HSiCl3 reduction of 2b and 8b to
bornylPh2P (1a) and isobornylPh2P (1b) as well as α-fench- 1b and 8b, respectively, made possible the assignment of
ylPh2P (7a) and β-fenchylPh2P (7b) with endo/exo ratios of the 31P NMR chemical shifts of the crude diphenylphos-
50:50 and 56:44, respectively.
phane mixtures.
Scheme 1. Synthesis of bornylphosphanes and related compounds.
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Eur. J. Org. Chem. 2010, 363–369

Reactions of the Bornyl and Fenchyl Grignard Reagents
Scheme 2. Synthesis of fenchylphosphanes and related compounds.
The reaction of the bornyl and fenchyl Grignard reagent and 37%, respectively.[9] Acid hydrolysis of these dia-
with PCl3 occurs with very little and modest diastereoselec- stereomeric alkylbis(diethylamino)phosphane mixtures pro-
tivity and afforded mixtures of the alkyldichlorophosphanes vided the phosphinic acids bornylP(O)(H)(OH) (5a) and
bornylPCl2 (3a) and isobornylPCl2 (3b) as well as α-fench- isobornylP(O)(H)(OH) (5b) as well as α-fenchylP(O)-
ylPCl2 (9a) and β-fenchylPCl2 (9b) with endo/exo ratios of (H)(OH) (11a) and β-fenchylP(O)(H)(OH) (11b). These ac-
55:45 and 25:75, respectively.[7] The crude yield of 3a/3b and ids were purified by acid base extraxction, however, all
9a/9b was 44% and 45%, respectively.[8] No attempts were attempts to separate 5a and 5b as well as 11a and 11b by
made to separate these diastereomeric mixtures, due to their recrystallization, column chromatography and HPLC
air sensitivity.
failed. Compounds 5a and 11b were isolated with dia-
The greatest diastereoselectivity was observed in the re- stereomeric purity of 92% and 88%, respectively, as color-
action of the bornyl and fenchyl Grignard reagent with less crystals in yields of 48% and 13%, respectively. The
(NEt2)2PCl, which produced mixtures of alkylbis(diethyl- reaction with dry HCl converted the same diastereomeric
amino)phosphanes bornylP(NEt2)2 (4a) and isobornylP- alkylbis(diethylamino)phosphane mixtures into the chloro-
(NEt2)2 (4b) as well as α-fenchylP(NEt2)2 (10a) and β-fench- phosphanes bornylPCl2 (3a) and isobornylPCl2 (3b) as well
ylP(NEt2)2 (10b) with endo/exo ratios of 96:4 and 6:94, as α-fenchylPCl2 (9a) and β-fenchylPCl2 (9b) without affect-
respectively.[7] The crude yield of 3a/3b and 9a/9b was 79% ing the endo/exo ratios. Oxidation of the latter with H2O2
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J. Beckmann, A. Schütrumpf
FULL PAPER
The crude phosphonic acid mixtures were purified by acid
base extraction and recrystallization. Compounds 6a and
12b were isolated pure as colorless crystals in yields of 69
and 33%, respectively. The molecular structure of 6a is
shown in Figure 4 and confirms the absolute and relative
configuration of the bornyl group, 12b is shown in Figure 5.
Figure 1. Structure of exo-isobornyldiphenylphosphane oxide (2b)
showing 30% probability displacement ellipsoids and the number-
ing scheme.
Figure 4. Structure of endo-bornylphosphonic acid (6a) showing
30% probability displacement ellipsoids and the numbering
scheme.
Figure 5. Structure of exo-β-fenchylphosphonic acid (12b) showing
30% probability displacement ellipsoids and the numbering
scheme.
Figure 2. Structure of endo-α-fenchyldiphenylphosphane oxide (8a)
showing 30% probability displacement ellipsoids and the number-
ing scheme.
Conclusions
The reactions of the bornyl and fenchyl Grignard rea-
gents with the chlorophosphanes, Ph2PCl, PCl3 and (Et2N)2-
PCl, respectively, provided diastereomeric mixtures of bor-
nylphosphanes and isobornylphosphanes as well as α-fen-
chylphosphanes and β-fenchylphosphanes. The diastereo-
selectivity of these reactions is entirely independent of the
initial endo/exo ratio of the Grignard reagent, which implies
that the stereochemical information of the α-carbon atoms
is at least partly lost, most likely at the stage of intermedi-
ary formed bornyl and fenchyl radicals.[10] A possible sub-
stitution mechanism that accounts for radical intermediates
involves an SET transfer between the Grignard reagent to
the chlorophosphanes prior to combination of the radical
pairs formed (“electron motion precedes nuclear mo-
tion”).[2] This SET mechanism may compete with the com-
monly accepted SN2 mechanism for substitution reaction
at phosphorus(III). Attempts to identify possible radical or
Figure 3. Structure of exo-β-fenchyldiphenylphosphane oxide (8b)
showing 30% probability displacement ellipsoids and the number-
ing scheme.
produced the corresponding phosphonic acids born- hypercoordinated phosphorus intermediates by low tem-
ylP(O)(OH)2 (6a) and isobornylP(O)(OH)2 (6b) as well as perature 31P NMR spectroscopy failed. The diastereoselec-
α-fenchylP(O)(OH)2 (12a) and β-fenchylP(O)(OH)2 (12b). tivity is modest for Ph2PCl (0% and 12% de) and PCl3
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Reactions of the Bornyl and Fenchyl Grignard Reagents
distilled while toluene (50 mL) was constantly added to replace the
original solvent THF. The temperature was slowly raised to 111 °C
and kept there for 12 h. The yield determined by titration was be-
tween 65 and 75%.[15]
(10% and 50% de) as can be expected if radical intermedi-
ates are involved, but surprisingly high for (NEt2)2PCl. In
this case, the diastereoselectivity (92% and 88% de) even
exceeds that of the Grignard formation (34% and 60%
de).[4] No definitive explanation can be given for this excep-
tionally high diastereoselectivity at this stage. However, the
Reaction of the (epimerized) Bornyl and Fenchyl Grignard Reagent
with Ph2PCl, PCl3 and (NEt2)2PCl: The appropriate Grignard rea-
different diastereoselectivities may be correlated with the gent (11.6 mmol) was slowly added to a solution of the chlorophos-
LUMO levels[2] of the chlorophosphanes calculated at the
phane (Ph2PCl: 2.55 g; PCl3: 1.59 g; (NEt2)2PCl: 2.44 g; 11.6 mmol)
MP2/6-311+ g(2d,p) level of theory,[11] which increases in
in THF (20 mL). The mixture was stirred for 12 h at room tempera-
ture before most of the solvent was removed in vacuo to leave an
the order Ph2PCl (1.5508 eV) Ͻ PCl3 (1.5511 eV) Ͻ (Et2N)2-
oily suspension. Hexane (20 mL) was added and the colourless pre-
PCl (1.5984 eV), respectively. One other possible reason of
cipitate filtered off. Again, the solvent was removed in vacuo to
the high diastereoselectivity of reactions involving (NEt2)2-
afford the crude products as oils. At this stage the crude reaction
PCl may involve the initial formation of a Lewis pair com-
plex (NǞMg) between (NEt2)2PCl and the Grignard rea-
gent prior to the substitution reaction that locks the reac-
tive centers into favorable positions. It is noteworthy that
the reaction of the fenchyl Grignard reagent with (NEt2)2-
PCl provides the thermodynamically less favored exo dia-
stereomer β-fenchylP(NEt2)2 (10b) in large excess, which
points to a kinetically controlled reaction pathway. The
same observation was made for the formation of the fenchyl
Grignard reagent.[4] Apparently, the reactions involve the
same radical intermediate, namely the fenchyl radical,
which has a strong bias on the formation of exo products.
In summary, our results suggest that the commonly ac-
cepted SN2 mechanism for substitution reactions at chloro-
phosphanes[12] is not (exclusively) operative in case of sec.
Grignard reagents. The investigated reactions provide evi-
dence to suggest that an SET mechanism involving free rad-
icals is at least partially operative.[13]
mixtures were investigated by 31P NMR spectroscopy (refer to the
text and references for details).
Synthesis of the Alkyldiphenylphosphane Oxides bornylPh2PO (2a)
and isobornylPh2PO (2b) as well as α-fenchylPh2PO (8a) and β-
fenchylPh2PO (8b): To the crude alkyldiphenylphosphanes (1a/1b
or 7a/7b) were dissolved in diethyl ether (100 mL), water (30 mL)
and hydrogen peroxide (30 mL, 33%) were added and the two layer
mixture vigorously stirred for 1 h. The layers were separated, the
organic layer washed with water (2ϫ40 mL) and dried with
Na2SO4. After removal of the solvent under reduced pressure, the
crude product was obtained as oil. The diastereomers were sepa-
rated by column chromatography (silica; hexane/ethyl acetate = 1:1
for 2a/2b and 2:1 for 8a/8b). Crystallization from hexane/dichloro-
methane afforded colorless crystals.
2a: Yield 0.56 g, 1.65 mmol, 14%; m.p. 162 °C. [α]D = 47.2 (c =
3.1; CHCl3). 1H NMR (CDCl3): δ = 7.82–7.74 (m, 4 H; Ph), 7.43–
7.36 (m, 6 H; Ph), 2.64–2.59 (m, 2 H; 2-H, 6A-H), 2.93–1.85 (m, 1
H; 3-H), 1.76–1.64 (m, 3 H; 3-H, 4-H, 5-H), 1.45–1.40 (m, 1 H; 5-
H), 1.31–1.26 (m, 1 H; 6S-H), 0.89 (s, 3 H; 9-H), 0.78 (s, 3 H; 8-
H), 0.41 (s, 3 H; 10-H) ppm. 13C{1H} NMR (CDCl3): δ = 135.2
(d, 1J(13C-31P) = 95 Hz; Ph), 134.4 (d, 1J(13C-31P) = 95 Hz; Ph),
131.0 (d, 4J(13C-31P) = 3 Hz; Ph), 130.7 (d, 2J(13C-31P) = 70 Hz;
Ph), 130.6 (d, 2J(13C-31P) = 70 Hz; Ph), 128.3 (d, 3J(13C-31P) =
Experimental Section
General Considerations: All operations were performed under ar-
gon using standard Schlenk and vacuum line techniques. Isobornyl
chloride or β-fenchyl chloride were obtained from commercially
available (1S)-(–)-endo-borneol and (1R)-(+)-endo-α-fenchol by the
Appel reaction using CCl4/PPh3. Bis(diethylamino)chlorophos-
phane (Et2N)2PCl was prepared according to a published pro-
3
3
25 Hz, Ph), 128.2 (d, J(13C-31P) = 25 Hz; Ph), 50.6 (d, J(13C-31P)
= 11 Hz, C-7), 49.6 (d, 2J(13C-31P) = 3 Hz; C-1), 44.7 (d, 3J(13C-
31P) = 3 Hz; C-4), 42.1 (d, 1J(13C-31P) = 76 Hz; C-2), 30.8 (C-3),
30.6 (d, (3J(13C-31P) = 5 Hz; C-6), 27.7 (C-5), 18.5 (C-9), 18.2 (C-
8), 15.8 (C-10) ppm. 31P{1H} NMR (CDCl3): δ = 31.1 (1J(31P-13C)
1
cedure.[14] 31P-, 13C- and H NMR spectra were collected using a
= 94, 1J(31P-13C) = 76 Hz) ppm. IR (KBr): ν(P=O): 1178 cm–1.
˜
Jeol JNM-LA 400 FT spectrometer and a Jeol Eclipse+ 500 FT
spectrometer. Chemical shifts are given in ppm relative to Me4Si
C22H27OP (338.42): calcd. C 78.08, H 8.04; found C 78.06, H 7.98.
1
and H3PO4 (aq.). The assignment of the 13C- and H NMR reso-
2b: Yield 0.61 g, 1.80 mmol, 15%; m.p. 166–167 °C. [α]D = 62.9 (c
= 5.6; CHCl3). 1H NMR (CDCl3): δ = 7.91–7.87 (m, 2 H; Ph),
7.78–7.74 (m, 2 H; Ph), 7.42–7.40 (m, 3 H; Ph), 7.36–7.34 (3 H,
Ph), 2.57–2.52 (m, 1 H; 2-H), 2.00–1.90 (m, 1 H; 3-H), 1.82–1.75
(m, 1 H; 5-H), 1.68–1.66 (m, 1 H; 5-H), 1.60–1.52 (m, 1 H; 6S-H),
1.35–1.29 (m, 1 H, 6A-H), 1.25–1.69 (m, 5 H; 3-H, 5-H, 9-H), 0.80
(s, 3 H, 8-H), 0.74 (s, 3 H, 10-H) ppm. 13C{1H} NMR (CDCl3): δ
= 135.5 (d, 1J(13C-31P) = 96 Hz; Ph), 134.7 (d, 1J(13C-31P) = 96 Hz;
Ph), 130.7 (d, 2J(13C-31P) = 33 Hz; Ph), 130.7 (d, 2J(13C-31P) =
nances was achieved using standard 2D NMR techniques including
1H-1H-COSY, 1H-1H-NOESY, 1H-13C-HMBC and 1H-13C-
HMQC. Optical rotations were measured on Perkin–Elmer 241 and
Schmidt & Haensch UniPol L1000 polarimeters. Microanalyses
were obtained from a Vario EL elemental analyzer. Infrared spectra
were recorded using Nexus FT-IR spectrometer with a Smart Dur-
aSamplIR.
Synthesis of the Bornyl and Fenchyl Grignard Reagent: A solution
of isobornyl chloride or β-fenchyl chloride (2.00 g, 11.6 mmol) in
THF (20 mL) was slowly added to a suspension of activated Mg
turnings (0.4) g, 17.4 mmol) in THF (5 mL). After the addition was
completed, the mixture was heated under reflux for 12 h. Prior to
use, the clear solution was separated from the excess of Mg via
cannula. The yield determined by titration was about 80%.[15]
4
3
33 Hz; Ph), 130.6 (d, J(13C-31P) = 3 Hz; Ph), 128.3 (d, J(13C-31P)
= 11 Hz; Ph), 128.2 (d, J(13C-31P) = 11 Hz; Ph), 50.7 (d, J(13C-
31P) = 2 Hz; C-7), 50.0 (C-1), 45.6 (d, 1J(13C-31P) = 72 Hz; C-2),
45.0 (d, 3J(13C-31P) = 4.1 Hz; C-4), 41.5 (d, 3J(13C-31P) = 13 Hz;
C-6), 31.8 (d, (2J(13C-31P) = 4 Hz; C-3), 27.2 (C-5), 20.6 (C-9), 20.1
(C-8), 16.4 (3J(13C-31P) = 4 Hz; C-10) ppm. 31P{1H} NMR
(CDCl3): δ = 34.2 (1J(31P-13C) = 95, 1J(31P-13C) = 71 Hz) ppm. IR
3
3
Synthesis of the epimerized Bornyl and Fenchyl Grignard Reagent:
(KBr): ν(P=O): 1178 cm–1. C H OP (338.42): calcd. C 78.08, H
˜
22 27
A solution of the bornyl or fenchyl Grignard reagent was slowly
8.04; found C 78.08, H 8.02.
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J. Beckmann, A. Schütrumpf
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8a: Yield 0.76 g, 2.25 mmol, 20%; m.p. 241–243 °C. [α]D = 10.5 (c 1J(1H-31P) = 534 Hz, 1 H; P–H), 1.99–1.97 (m, 1 H; 7-H), 1.77–
= 5.9; CHCl3). 1H NMR (CDCl3): δ = 7.88–7.79 (m, 4 H; o-Ar- 1.70 (m, 1 H; 5-H), 1.69–1.67 (m, 1 H; 4-H), 1.52–1.45 (m, 1 H; 5-
H), 7.35–7.29 (m, 6 H; Ar-H), 2.70–2.64 (m, 1 H; 6A-H), 2.13–1.12
(m, 1 H; 2-H), 1.90–1.85 (m, 1 H; 5A-H), 1.59–1.57 (m, 2 H; 4-H,
7-H), 1.39–1.32 (m, 1 H, 5S-H), 1.06–1.02 (m, 1 H; 7-H), 0.99 (br.
H), 1.40–1.37 (m, 1 H; 6-H), 1.35 (br. s, 3 H; 10-H), 1.32 (s, 3 H;
9-H), 1.29–1.25 (m, 2 H; 6-H, 2-H), 1.13 (s, 3 H; 8-H), 1.11–1.09
1
(m, 1 H; 7-H) ppm. 13C{1H} NMR (CDCl3): δ = 56.1 (d, J(13C-
s, 3 H; 8-H), 0.98–0.94 (m, 1 H; 6-H), 0.93 (br. s, 3 H; 9-H), 0.54 31P) = 95 Hz; C-2), 49.3 (d, 3J(13C-31P) = 3 Hz; C-4), 48.2 (C-1),
(br. s, 3 H; 10-H) ppm. 13C{1H} NMR (CDCl3): δ = 136.4 (d,
44.2 (C-7), 43.0 (d, (2J(13C-31P) = 5 Hz; C-3), 40.2 (d, J(13C-31P)
3
1J(13C-31P) = 92 Hz; Ph), 130.7 (m, Ph), 128.1 (d, 3J(13C-31P) = = 15 Hz; C-6), 28.6 (d, 3J(13C-31P) = 4 Hz; C-8), 26.0 (d, 3J(13C-
1
2
10 Hz; Ph), 53.7 (d, J(13C-31P) = 70 Hz; C-2), 50.8 (d, J(13C-31P) 31P) = 14 Hz; C-9), 25.2 (C-5), 19.6 (d, 3J(13C-31P) = 7.3 Hz; C-10)
= 2 Hz; C-1), 50.2 (d, 3J(13C-31P) = 4 Hz; C-4), 47.5 (d, 3J(13C-31P) ppm. 31P{1H} NMR (CDCl3): δ = 37.6 (1J(31P-13C-2) = 93.3 Hz)
= 15 Hz; C-7), 42.6 (C-3), 33.2 (d, (3J(13C-31P) = 4 Hz; C-9), 29.7 ppm. IR (KBr): ν(P=O): 1198 cm–1; (P–H): 2357 cm–1. C H O P
˜
10 19
2
(C-6), 25.8 (C-5), 23.2 (d, (3J(13C-31P) = 7 Hz; C-8), 23.1 (C-10) (202.23): calcd. C 59.39, H 9.47; found C 59.16, H 9.66.
ppm. 31P{1H} NMR: δ = 27.7 (1J(31P-13C) = 93, 1J(31P-13C) =
Synthesis of Alkyldichlorophosphanes bornylPCl2 (3a) and β-fench-
ylPCl2 (9b): The crude alkylbis(diethylamino)phosphanes (4a/4b or
10a/10b) were dissolved in diethyl ether (200 mL) cooled to 0 °C
before gaseous hydrogen chloride was bubbled through the solution
for about 5 min. The voluminous precipitate was removed by fil-
tration. The solvent was removed in vacuo to leave the crude alkyl-
dichlorophosphanes (3a/3b or 9a/9b) as colorless oils.
70 Hz) ppm. IR (KBr): ν(P=O): 1187 cm–1. C H OP (338.42):
˜
22 27
calcd. C 78.08, H 8.04; found C 78.09, H 8.11.
8b: Yield 0.36 g, 1.06 mmol, 9%; m.p. 241–243 °C. [α]D = –74.6 (c
= 3.8; CHCl3). 1H NMR (CDCl3): δ = 7.85–7.80 (m, 4 H; Ph),
7.37–7.34 (m, 6 H; Ph), 2.29–2.27 (m, 1 H; 7-H), 2.18 (m, 1 H; 2-
H), 1.82–1.77 (m, 1 H; 5A-H), 1.63–1.62 (m, 1 H; 6S-H), 1.41–1.34
(m, 1 H; 5S-H), 1.35–1.31 (m, 1 H; 6A-H), 1.09 (br. s, 3 H; 9-H),
1.08–1.06 (m, 1 H; 7-H), 0.97 (br. s, 3 H; 8-H), 0.92 (br. s, 3 H; 10-
H) ppm. 13C{1H} NMR (CDCl3): δ = 138.1 (d, 1J(13C-31P) =
92 Hz; Ph), 137.5 (d, 1J(13C-31P) = 92 Hz; Ph), 130.5 (d, 4J(13C-
31P) = 3 Hz; Ph), 130.1 (d, 2J(13C-31P) = 54 Hz; Ph), 130.0 (d,
Synthesis of Alkylphosphonic Acids bornylP(O)(OH)2 (6a) and β-
fenchylP(O)(OH)2 (12b): To the crude alkyldichlorophosphanes
(3a/3b or 9a/9b) hydrogen peroxide (30 mL, 33%) was carefully
added and the mixture heated under reflux for 2 h. Diethyl ether
(50 mL) and aqueous NaOH solution (50 mL, 1 ) were added the
mixture was vigorously stirred for 1 h before the layers were sepa-
rated. The ether layer contained the impurities and was discarded.
The crude product was recovered by acidification of the aqueous
layer with hydrochloric acid (50 mL, 24%) and extraction with di-
ethyl ether (2ϫ50 mL). The combined organic layers were dried
with Na2SO4 and the solvent was removed in vacuo. Crystallization
from dichloromethane (6a) and ethanol (12b) furnished colorless
crystals.
3
2J(13C-31P) = 56 Hz; Ph), 128.2 (d, J(13C-31P) = 10 Hz; Ph), 128.1
(d, 3J(13C-31P) = 10 Hz; Ph), 53.8 (d, 1J(13C-31P) = 69 Hz; C-2),
50.1 (d, 3J(13C-31P) = 3 Hz; C-4), 50.0 (C-1), 44.8 (C-7), 44.2 (d,
2J(13C-31P) = 5 Hz; C-3), 40.8 (d, 3J(13C-31P) = 11 Hz; C-6), 29.2
(d, (3J(13C-31P) = 3 Hz; C-8), 26.3 (d, (3J(13C-31P) = 10 Hz; C-9),
25.3 (C-5), 21.9 (3J(13C-31P) = 4 Hz; C-10) ppm. 31P{1H} NMR
1
(CDCl3): δ = 28.0 (1J(31P-13C) = 93, J(31P-13C-2) = 69 Hz) ppm.
IR (KBr): ν(P=O): 1177 cm–1. C H OP (338.42): calcd. C 78.08,
˜
22 27
H 8.04; found C 78.02, H 8.25.
6a: Yield 1.75 g, 8.00 mmol, 69%; m.p. 201 °C. [α]D = –15.7 (c =
0.83; EtOH). 1H NMR (500 MHz, CDCl3): δ = 10.31 (s, 2 H; OH),
Synthesis of Alkylphosphinic Acids bornylP(O)(H)(OH) (5a) and β-
fenchylP(O)(H)(OH) (11b): The crude alkylbis(diethylamino)phos-
phanes (4a/4b or 10a/10b) were dissolved in diethyl ether (50 mL)
and hydrochloric acid (50 mL, 24%) was added. The mixture
stirred for 2 h before the layers were separated. The organic layer
was washed with an aqueous NaOH solution (50 mL, 1 ) for 2 h
before the layers were again separated. The organic layer contained
only the impurities and was discarded. The crude product was reco-
vered by acidification of the aqueous layer with hydrochloric acid
(50 mL, 24%) and extraction with diethyl ether (2ϫ50 mL). The
combined organic layers were dried with Na2SO4 and the solvent
was removed in vacuo. Crystallization from dichloromethane pro-
vided colorless microcrystalline products. All attempts to remove
the minor epimers by fractional crystallization, column chromatog-
raphy and HPLC failed.
1
6.9 (d; J(1H-31P) = 571.0 Hz, 1 H P–H), 2.07–2.02 (m, 1 H, 2-H),
2.00–1.89 (m, 2 H; 3-H, 6-H), 1.67–1.61 (m, 2 H; 4-H, 5-H), 1.52–
1.3 (m, 1 H; 3-H), 1.36–1.31 (m, 1 H, 6-H), 1.24–1.18 (m, 1 H, 5-
H), 0.95 (br. s, 3 H, 10-H), 0.79 (br. s, 3 H, 8-H oder 9-H), 0.78
(3H. br. s, 8-H oder 9-H) ppm. 13C{1H} NMR (126 MHz, CDCl3):
δ = 49.6 (d, 3J(13C-31P) = 17.6 Hz; C-7), 48.2 (d, 2J(13C-31P) =
2.0 Hz; C-1), 44.8 (d, 3J(13C-31P) = 5.1 Hz, C-4), 40.1 (d, 1J(13C-
31P) = 149.5 Hz, C-2), 30.6 (d, (3J(13C-31P) = 6.2 Hz, C-6), 30.4 (C-
3), 27.6 (C-5), 18.5 (C-8 oder C-9), 18.4 (C-8 oder C-9), 15.0 (C-
10) ppm. 31P{1H} NMR (162 MHz, CDCl3): δ = 38.8 (1J(31P-13C-
2) = 149.6 Hz) ppm. IR (KBr): ν(P=O): 1166 cm–1. C H O P
˜
10 19
3
(218.22): calcd. C 55.04, H 8.78; found C 54.92, H 8.44.
12b: Yield 0.83 g, 3.82 mmol, 33%; m.p. 233 °C. [α]D = –31.9 (c =
0.83; EtOH). 1H NMR (500 MHz, CD3OD): δ = 5.21 (s, 2 H; OH),
2.00–1.97 (m, 1 H, 7-H), 1.82–1.78 (m, 1 H, 5-H), 1.69–1.64 (1 H,
m. 4-H), 1.55–1.48 (m, 1 H, 5-H), 1.43–1.38 (m, 1 H, 6-H), 1.35–
1.32 (m, 3 H, 2-H, 6-H, 10-H), 1.30 (s, 3 H, 9-H), 1.13 (s, 3 H, 8-
H), 1.10–1.07 (m, 7-H, 1 H) ppm. 13C{1H} NMR (126 MHz,
CD3OD): δ = 56.9 (d, 1J(13C-31P) = 137.0 Hz, C-2), 50.9 (d, 3J(13C-
31P) = 5.2 Hz, C-4), 48.8 (C-1), 45.0 (C-7), 43.6 (d, (2J(13C-31P) =
5a: Yield 1.21 g, 5.54 mmol, 48%. Purity 92% de. [α]D = –15.2 (c
1
= 4.27; CHCl3). H NMR (CDCl3): δ = 12.05 (s, 1 H; OH), 6.95
1
(d, J(1H-31P) = 571 Hz, 1 H; P–H), 2.07–1.95 (m, 2 H; 2-H, 3-H),
1.81–1.68 (m, 3 H; 4-H, 5-H, 6-H), 1.51–1.38 (m, 2 H; 3-H, 6-H),
1.24–1.39 (m, 1 H; 5-H), 1.03 (br. s, 3 H, 10-H), 0.85 (m, 3 H, 9-
H), 0.84 (s, 3 H; 8-H) ppm. 13C{1H} NMR (CDCl3): δ = 50.1 (d,
3
3J(13C-31P) = 11 Hz, C-7), 48.3 (C-1), 44.7 (d, J(13C-31P) = 4 Hz;
3
3
4.1 Hz, C-3), 41.8 (d, J(13C-31P) = 14.5 Hz, C-6), 28.6 (d, J(13C-
C-4), 42.9 (d, 1J(13C-31P) = 102 Hz; C-2), 30.9 (d, (3J(13C-31P) =
10 Hz; C-6), 29.5 (C-3), 27.9 (C-5), 18.2 (C-8 or C-9), 17.9 (C-8 or
C-9), 15.0 (C-10) ppm. 31P{1H} NMR (CDCl3): δ = 43.9 (1J(31P-
31P) = 4.1 Hz, C-8), 26.9 (d, J(13C-31P) = 10.3 Hz; C-9), 26.0 (C-
3
5), 21.1 (d, 3J(13C-31P) = 4.1 Hz; C-10) ppm. 31P{1H} NMR
(162 MHz, CDCl3): δ = 33.5 (1J(31P-13C-2) = 136.2 Hz) ppm. IR
13C) = 102 Hz) ppm. IR (KBr): ν(P=O): 1176 cm–1; (P–H):
˜
(KBr): ν(P=O): 1212 cm–1. C H O P (218.22): calcd. C 55.04, H
2361 cm–1. C10H19O2P (202.23): calcd. C 59.39, H 9.47; found C
59.19, H 9.54.
˜
10 19
3
8.78; found C 54.72, H 8.39.
11b: Yield 0.61 g, 2.95 mmol, 13%. Purity 88% de. [α]D = –29.4 (c
= 4.7; CHCl3). 1H NMR (CDCl3): δ = 11.65 (s, 1 H; OH), 7.20 (d;
Supporting Information (see also the footnote on the first page of
this article): General details, bond parameters as well as crystal and
368
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 363–369

Reactions of the Bornyl and Fenchyl Grignard Reagents
3
refinement data of the X-ray structure analyses; indicative J(31P-
(2%; 10a) as well as 2 minor intense signals and 1 intense signal
at δ = 128.1 (4%), 115.8 (6%), 83.8 (35%) that were not as-
signed.
CC-13C) couplings related to the Karplus relation.
CCDC-749942 (2b), -749943 (8a), -749944 (8b), -749945 (6a),
-749946 (12b) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[10] Radical intermediates are supported by MS spectrometry,
which points to 2,2Ј-bibornanes (m/z = 274) as by-products.
[11] a) Full geometry optimizations were applied to the chlorophos-
phanes Ph2Cl, PCl3 and NEt2)2PCl at the MP2/6-311+ g(2d,p)
level of theory. Frequency analyses assured that the stationary
points were true minima of the hyperpotential energy surface.
b) All calculations were performed using Gaussian: M. J.
Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, J. A. Montgomery, Jr., T. Vreven,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratch-
ian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C.
Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dap-
prich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick,
A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q.
Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin,
D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayak-
kara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M.
W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, revision D.01,
Gaussian, Inc., Wallingford, CT, 2004.
[12] a) E. P. Kyba, J. Am. Chem. Soc. 1975, 97, 2554–2555; b) E. P.
Kyba, C. W. Hudson, Tetrahedron Lett. 1975, 1869–1872; c)
E. P. Kyba, J. Am. Chem. Soc. 1976, 98, 4805–4809; d) J. Omel-
anczuk, M. Mikolajczyk, J. Chem. Soc., Chem. Commun. 1976,
24, 1025–1026; e) M. Mikolajczyk, J. Omelanczuk, W. Perli-
kowska, Tetrahedron 1979, 1531–1536; f) M. Mikolajczyk, Pure
Appl. Chem. 1980, 52, 959–972; g) R. R. Holmes, Pentacoordi-
nated Phosphorous - Reaction Mechanism, ACS Monograph
176, American Chemical Society, Washington DC, 1980, vol.
II, Chapter 2; h) T. I. Solling, A. Pross, L. Radoma, Int. J.
Mass Spec. 2001, 210/211, 1–11; i) M. A. van Bochove, M.
Swart, F. M. Bickelhaupt, J. Am. Chem. Soc. 2006, 128, 10738–
10744; j) C. Fish, M. Green, R. J. Kilby, J. M. Lynam, J. E.
McGrady, D. A. Pantazis, C. A. Russell, A. C. Whitwood,
C. E. Willans, Angew. Chem. Int. Ed. 2006, 45, 3628–3631; k)
M. A. van Bochove, M. Swart, F. M. Bickelhaupt, ChemPhys-
Chem 2007, 8, 2452–2463; l) M. A. van Bochove, M. Swart,
F. M. Bickelhaupt, Phys. Chem. Chem. Phys. 2009, 11, 259–
267.
[1] Handbook of Grignard Reagents (Eds.: G. S. Silverman, P. E.
Rakita), Marcel Dekker, New York, 1996.
[2] R. W. Hoffmann, Chem. Soc. Rev. 2003, 32, 225–230, and refer-
ences cited therein.
[3] J. Beckmann, D. Dakternieks, M. Dräger, A. Duthie, Angew.
Chem. Int. Ed. 2006, 45, 6509–6512.
[4] J. Beckmann, A. Schütrumpf, Org. Biomol. Chem. 2009, 7, 41–
42.
[5] L. D. Quin, M. J. Gallagher, G. T. Cunkle, D. B. Chesnut, J.
Am. Chem. Soc. 1980, 102, 3136–3143.
[6] Reaction of the bornyl Grignard reagent with Ph2PCl: The 31
P
NMR spectrum (CDCl3) of the crude reaction mixture showed
3 assigned signals at δ = 80.0 (15%; Ph2PCl), –12.6 (29%; 1b)
and –15.8 (29%; 1a) as well as 8 minor intense signals at δ =
70.6 (4%), 42.7 (3%), 41.1 (3%), 30.1 (2%), 23.3 (8%), –17.9
(2%), –21.5 (3%) and –23.1 (3%) that were not assigned. Reac-
tion of the fenchyl Grignard reagent with Ph2PCl: The 31P
NMR spectrum (CDCl3) of the crude reaction mixture showed
3 assigned signals at δ = 79.9 (35%; Ph2PCl), –11.6 (27%, 7b)
and –17.9 (21%, 7a) as well as 5 minor intense signals at δ =
70.6 (5%), 42.8 (5%), 40.8 (2%), –23.6 (2%) and –24.5 (3%)
that were not assigned.
[7] The reaction of the bornyl Grignard reagent with PCl3 and
(Et2N)2PCl was already reported with very similar results;
however, the authors neither knew the composition of the bor-
nyl Grignard reagent nor drew any conclusions regarding the
substitution mechanism. A. Marinetti, F.-X. Buzin, L. Ricard,
J. Org. Chem. 1997, 62, 297–301.
[8] Reaction of the bornyl Grignard reagent with PCl3: The 31P
NMR spectrum (CDCl3) of the crude reaction mixture showed
3 assigned signals at δ = 215.8 (36%; PCl3), 198.7 (20%; 3b)
and 197.8 (24%; 3a) as well as 5 minor intense signals at δ =
205.4 (2%), 199.3 (2%), 189 (5%), 174.6 (6%), 170.7 (5%) that
were not assigned. Reaction of the fenchyl Grignard reagent
with PCl3: The 31P NMR spectrum (CDCl3) of the crude reac-
tion mixture showed 3 assigned signals at δ = 215.6 (25%,
PCl3), 209.8 (15%, 9a), 203.8 (40%, 9b) as well as 5 minor
intense signals at δ = 206.7 (3%), 206.1 (2%), 205.3 (2%), 199.8
(10%), 188.9 (3%) that were not assigned.
[13] a) A. Nakanishi, W. B. Bentrude, J. Am. Chem. Soc. 1978, 100,
6271–6273; b) W. G. Bentrude, Acc. Chem. Res. 1982, 15, 117–
125; c) W. G. Bentrude, M. Moriyama, H. D. Müller, A. E.
Sopchik, J. Am. Chem. Soc. 1983, 105, 6053–6061.
[9] Reaction of the bornyl Grignard reagent with (Et2N)2PCl: The
31P NMR spectrum (CDCl3) of the crude reaction mixture
showed 3 assigned signals at δ = 154.2 (14%; (Et2N)2PCl), 96.1
(6%; 4b) and 93.8 (73%; 4a) as well as 1 minor intense signal at
δ = 118.2 (7%) that were not assigned. Reaction of the fenchyl
Grignard reagent with (Et2N)2PCl: The 31P NMR spectrum
(CDCl3) of the crude reaction mixture showed 3 assigned sig-
nals at δ = 154.2 (18%, (Et2N)2PCl), 94.9 (35%; 10b) and 93.2
[14] R. B. King, P. M. Sundaram, J. Org. Chem. 1984, 49, 1784–
1789.
[15] A. Krasovskiy, P. Knochel, Synthesis 2006, 890–891.
Received: August 10, 2009
Published Online: December 2, 2009
Eur. J. Org. Chem. 2010, 363–369
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
369